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Tian T, Han H, Huang J, Ma J, Ran R. DBI as a Novel Immunotherapeutic Candidate in Colorectal Cancer: Dissecting Genetic Risk and the Immune Landscape via GWAS, eQTL, and pQTL. Biomedicines 2025; 13:1115. [PMID: 40426943 PMCID: PMC12109284 DOI: 10.3390/biomedicines13051115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2025] [Revised: 04/24/2025] [Accepted: 04/30/2025] [Indexed: 05/29/2025] Open
Abstract
Background: Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. Identifying drug targets associated with CRC is crucial for developing targeted therapies. Methods: MR (IVW, Wald ratio, weighted median, and MR-Egger) and SMR analyses were used to screen candidate genes associated with CRC risk. Further validation was performed using The Cancer Genome Atlas (TCGA) to assess gene expression patterns and prognostic significance. Additionally, immune infiltration analysis was conducted to characterize the tumor immune microenvironment. Drug prediction was performed to explore potential therapeutic interventions. Results: Eight genes were identified associated with CRC. IGFBP3, CD72, SERPINH1, CHRDL2, LRP11, and SPARCL1 were linked to an increased risk of CRC, whereas DBI and HYAL1 were associated with a decreased risk of CRC. Notably, DBI exhibited a potentially favorable immune profile, negatively correlated with Tregs and MDSCs while positively associated with activated CD8+ and CD4+ T cells. Conclusions: Eight genes were identified as associated with CRC, among which DBI exhibited a potential protective role, correlating with improved patient survival, enhanced immune activation, and increased responsiveness to immunotherapy. The remaining proteins demonstrated diverse and complex functions within the tumor immune microenvironment, providing novel insights for the development of precision diagnostics and immunotherapeutic strategies.
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Affiliation(s)
- Ting Tian
- Department of Clinical Laboratory, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430070, China; (T.T.); (J.M.)
| | - Huan Han
- Department of Clinical Laboratory, Institute of Translational Medicine, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei, China; (H.H.); (J.H.)
| | - Jingtao Huang
- Department of Clinical Laboratory, Institute of Translational Medicine, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei, China; (H.H.); (J.H.)
| | - Jun’e Ma
- Department of Clinical Laboratory, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430070, China; (T.T.); (J.M.)
| | - Ruoxi Ran
- Department of Clinical Laboratory, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430070, China; (T.T.); (J.M.)
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Panza P, Kim HT, Lautenschläger T, Piesker J, Günther S, Alayoubi Y, Cleaver O, Looso M, Stainier DYR. The lung microvasculature promotes alveolar type 2 cell differentiation via secreted SPARCL1. Stem Cell Reports 2025; 20:102451. [PMID: 40118055 PMCID: PMC12069885 DOI: 10.1016/j.stemcr.2025.102451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 02/15/2025] [Accepted: 02/17/2025] [Indexed: 03/23/2025] Open
Abstract
Lung endothelial cells (ECs) and pericytes are closely juxtaposed with the respiratory epithelium before birth and thus may have instructive roles during development. To test this hypothesis, we screened EC-secreted proteins for their ability to alter cell differentiation in alveolar organoids. We identified secreted protein acidic and rich in cysteine-like protein 1 (SPARCL1) as an extracellular matrix molecule that can promote alveolar type 2 (AT2) cell differentiation in vitro. SPARCL1-treated organoids display lysozyme upregulation and a doubling in the number of AT2 cells at the expense of intermediate progenitors. SPARCL1 also induces the upregulation of nuclear factor κB (NF-κB) target genes, and suppression of NF-κB activation in lung organoids blocked SPARCL1 effects. NF-κB activation by lipopolysaccharide (LPS) was sufficient to induce AT2 cell differentiation; however, pharmacological inhibition of the pathway alone did not prevent it. These data support a role for SPARCL1 and NF-κB in alveolar cell differentiation and suggest a potential value in targeting this signaling axis to promote alveolar maturation and regeneration.
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Affiliation(s)
- Paolo Panza
- Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany; Department of Medicine V, Internal Medicine, Infectious Diseases and Infection Control, Justus-Liebig University Giessen, Giessen, Germany; Member of the German Center for Lung Research, DZL-UGMLC; Member of the Excellence Cluster Cardio-Pulmonary Institute, CPI.
| | - Hyun-Taek Kim
- Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Till Lautenschläger
- Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Janett Piesker
- Scientific Service Group Microscopy, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Stefan Günther
- Deep Sequencing Platform, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Yousef Alayoubi
- Bioinformatics Core Unit, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | | | - Mario Looso
- Bioinformatics Core Unit, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Didier Y R Stainier
- Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany; Member of the German Center for Lung Research, DZL-UGMLC; Member of the Excellence Cluster Cardio-Pulmonary Institute, CPI.
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3
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Liu L, Han F, Deng M, Han Q, Lai M, Zhang H. Crosstalk between GLTSCR1-deficient endothelial cells and tumour cells promotes colorectal cancer development by activating the Notch pathway. Cell Death Differ 2025:10.1038/s41418-025-01450-6. [PMID: 39870803 DOI: 10.1038/s41418-025-01450-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 12/17/2024] [Accepted: 01/21/2025] [Indexed: 01/29/2025] Open
Abstract
Cancer stem cells (CSCs) typically reside in perivascular niches, but whether endothelial cells of blood vessels influence the stemness of cancer cells remains poorly understood. This study revealed that endothelial cell-specific GLTSCR1 deletion promotes colorectal cancer (CRC) tumorigenesis and metastasis by increasing cancer cell stemness. Mechanistically, knocking down GLTSCR1 induces the transformation of endothelial cells into tip cells by regulating the expression of Neuropilin-1 (NRP1), thereby increasing the direct contact and interaction between endothelial cells and tumour cells. In addition, GLTSCR1 inhibits JAG1 transcription by competing with acetylated p65(Lys-310) to bind to the BRD4 interaction site. Therefore, GLTSCR1 deficiency increases JAG1 expression in endothelial cells. Subsequently, increased JAG1 levels on tip cell membranes bind to Notch on CRC cell membranes, activating the Notch signalling pathway in tumour cells and increasing CRC cell stemness. Taken together, our findings highlight the roles of endothelial cells in CRC development.
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Affiliation(s)
- Lu Liu
- Department of Pathology and International Institutes of Medicine, The Fourth Affiliated Hospital (Yiwu), Zhejiang University School of Medicine, Hangzhou, 310058, China
- Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Sciences (2019RU042), Hangzhou, 310058, China
| | - Fengyan Han
- School of Basic Medical Sciences, The Fourth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China.
| | - Mengli Deng
- Department of Pathology and International Institutes of Medicine, The Fourth Affiliated Hospital (Yiwu), Zhejiang University School of Medicine, Hangzhou, 310058, China
- Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Sciences (2019RU042), Hangzhou, 310058, China
| | - Qizheng Han
- Department of Pathology and International Institutes of Medicine, The Fourth Affiliated Hospital (Yiwu), Zhejiang University School of Medicine, Hangzhou, 310058, China
- Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Sciences (2019RU042), Hangzhou, 310058, China
| | - Maode Lai
- Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Sciences (2019RU042), Hangzhou, 310058, China.
- Department of Pathology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China.
| | - Honghe Zhang
- Department of Pathology and International Institutes of Medicine, The Fourth Affiliated Hospital (Yiwu), Zhejiang University School of Medicine, Hangzhou, 310058, China.
- Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Sciences (2019RU042), Hangzhou, 310058, China.
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Yong Y, Demmler R, Zohud BA, Fang Q, Zhang T, Zhou Y, Petter K, Flierl C, Gass T, Geppert CI, Merkel S, Schellerer VS, Naschberger E, Stürzl M. AMIGO2 characterizes cancer-associated fibroblasts in metastatic colon cancer and induces the release of paracrine active tumorigenic secretomes. J Pathol 2025; 265:14-25. [PMID: 39523830 PMCID: PMC11638658 DOI: 10.1002/path.6363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 07/24/2024] [Accepted: 10/01/2024] [Indexed: 11/16/2024]
Abstract
Secretomes of cancer-associated fibroblasts (CAFs) in colorectal cancer (CRC) contribute to malignancy. Detailed knowledge is available on the components and functions of CAF secretomes. Little is known about the regulation of CAF secretomes. Here, we searched for receptor-like membrane-bound molecules in CAFs, which may regulate the production and release of tumor-activating secretomes. The adhesion molecule with Ig-like domain 2 (AMIGO2) was significantly upregulated in cultivated CAFs compared to normal tissue-associated fibroblasts (NAFs), and this was confirmed in patient-derived tissues. AMIGO2 expression was low or absent in healthy colon, significantly increased in fibroblasts of primary CRC, and highest in the stromal tissues of CRC-derived liver metastases. AMIGO2 expression in CAFs correlated with a higher T-category, increased lymph node metastasis, progressed tumor stages and was associated with reduced survival in different cohorts of CRC patients. Interestingly, AMIGO2 expression was induced by transforming growth factor-β and higher in female patients, who exhibit a more aggressive disease course. In functional studies, conditioned media of NAFs with experimentally induced AMIGO2 overexpression enhanced proliferation and migration of different CRC tumor cells, while siRNA-mediated inhibition of AMIGO2 in CAFs attenuated these effects. Accordingly, therapeutic inhibition of the receptor-like AMIGO2 protein in CRC CAFs could prevent tumorigenic secretomes in CRC. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Yongsong Yong
- Division of Molecular and Experimental Surgery, Department of SurgeryUniversitätsklinikum Erlangen, Friedrich‐Alexander‐Universität (FAU) Erlangen‐NürnbergErlangenGermany
- Xinghua People's Hospital Affiliated to Yangzhou UniversityTaizhouPR China
| | - Richard Demmler
- Division of Molecular and Experimental Surgery, Department of SurgeryUniversitätsklinikum Erlangen, Friedrich‐Alexander‐Universität (FAU) Erlangen‐NürnbergErlangenGermany
| | - Bisan Abdalfatah Zohud
- Division of Molecular and Experimental Surgery, Department of SurgeryUniversitätsklinikum Erlangen, Friedrich‐Alexander‐Universität (FAU) Erlangen‐NürnbergErlangenGermany
| | - Qi Fang
- Division of Molecular and Experimental Surgery, Department of SurgeryUniversitätsklinikum Erlangen, Friedrich‐Alexander‐Universität (FAU) Erlangen‐NürnbergErlangenGermany
| | - Tong Zhang
- Xinghua People's Hospital Affiliated to Yangzhou UniversityTaizhouPR China
| | - Yonghua Zhou
- Xinghua People's Hospital Affiliated to Yangzhou UniversityTaizhouPR China
| | - Katja Petter
- Division of Molecular and Experimental Surgery, Department of SurgeryUniversitätsklinikum Erlangen, Friedrich‐Alexander‐Universität (FAU) Erlangen‐NürnbergErlangenGermany
| | - Christian Flierl
- Division of Molecular and Experimental Surgery, Department of SurgeryUniversitätsklinikum Erlangen, Friedrich‐Alexander‐Universität (FAU) Erlangen‐NürnbergErlangenGermany
| | - Tobias Gass
- Division of Molecular and Experimental Surgery, Department of SurgeryUniversitätsklinikum Erlangen, Friedrich‐Alexander‐Universität (FAU) Erlangen‐NürnbergErlangenGermany
| | - Carol I Geppert
- Institute of Pathology, Universitätsklinikum ErlangenFriedrich‐Alexander‐Universität (FAU) Erlangen‐NürnbergErlangenGermany
| | - Susanne Merkel
- Department of Surgery, Universitätsklinikum ErlangenFriedrich‐Alexander‐Universität (FAU) Erlangen‐NürnbergErlangenGermany
| | - Vera S Schellerer
- Department of Surgery, Universitätsklinikum ErlangenFriedrich‐Alexander‐Universität (FAU) Erlangen‐NürnbergErlangenGermany
- Department of Pediatric SurgeryUniversity Medicine GreifswaldGreifswaldGermany
| | - Elisabeth Naschberger
- Division of Molecular and Experimental Surgery, Department of SurgeryUniversitätsklinikum Erlangen, Friedrich‐Alexander‐Universität (FAU) Erlangen‐NürnbergErlangenGermany
- CCC Erlangen‐EMN: Comprehensive Cancer Center Erlangen‐EMN (CCC ER‐EMN)Universitätsklinikum Erlangen, Friedrich‐Alexander‐Universität (FAU) Erlangen‐NürnbergErlangenGermany
- CCC WERA: Comprehensive Cancer Center Alliance WERA (CCC WERA)ErlangenGermany
- BZKF: Bavarian Cancer Research Center (BZKF)ErlangenGermany
| | - Michael Stürzl
- Division of Molecular and Experimental Surgery, Department of SurgeryUniversitätsklinikum Erlangen, Friedrich‐Alexander‐Universität (FAU) Erlangen‐NürnbergErlangenGermany
- CCC Erlangen‐EMN: Comprehensive Cancer Center Erlangen‐EMN (CCC ER‐EMN)Universitätsklinikum Erlangen, Friedrich‐Alexander‐Universität (FAU) Erlangen‐NürnbergErlangenGermany
- CCC WERA: Comprehensive Cancer Center Alliance WERA (CCC WERA)ErlangenGermany
- BZKF: Bavarian Cancer Research Center (BZKF)ErlangenGermany
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5
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Chen X, Guo H, Li X, Liu Y, Li X, Cui Z, Ma H, He J, Zeng Z, Zhang H. Elevated Serum Extracellular Vesicle-Packaged SPARC in Hypertension: A Cross-Sectional Study in a Middle-Aged and Elderly Population. J Clin Hypertens (Greenwich) 2025; 27:e14954. [PMID: 39632586 PMCID: PMC11773675 DOI: 10.1111/jch.14954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 11/06/2024] [Accepted: 11/15/2024] [Indexed: 12/07/2024]
Abstract
Elevated blood pressure has previously been associated with increased levels of circulating extracellular vesicles (EVs). However, studies on the relevance of EV cargos to hypertension are limited. Secreted protein acidic and rich in cysteine (SPARC) is involved in many metabolic diseases and endothelial dysfunction pathological processes. This study aimed to explore the association of serum EV-derived SPARC with hypertension incidence. We conducted a cross-sectional study on 125 Chinese, including 76 hypertension patients and 49 normotensive patients. Serum EVs were prepared via ultracentrifugation. The concentrations of serum EV-derived SPARC and serum SPARC were measured by Luminex Assay. The correlations between serum EV-derived SPARC and clinical variables were analyzed. Multivariate logistic regression analysis determined the association of serum EV-derived SPARC levels with hypertension. Interaction subgroup analysis was used to evaluate the interaction of the relevant baselines on the association between serum EV-derived SPARC levels and hypertension. Our findings revealed that the levels of SPARC derived from serum EVs were markedly elevated in individuals with hypertension, averaging 20.60 ng/mL (p < 0.01), when contrasted with the levels observed in normotensive subjects, which were 14.25 ng/mL (p < 0.01) in average. Multivariate logistic regression analysis revealed that serum EV-derived SPARC levels were positively associated with hypertension (odds ratio [OR] 1.095; 95% confidence interval [CI] = 1.031-1.163; p value, 0.003), after adjusting for confounding factors. Interaction subgroup analysis demonstrated that no significant interaction with hypertension was observed for any particular covariate. The present study reveals that the elevated levels of serum EV-derived SPARC were independently associated with hypertension.
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Affiliation(s)
- Xueying Chen
- Beijing An Zhen HospitalCapital Medical University, The Key Laboratory of Remodeling Cardiovascular Diseases, Ministry of Education; Collaborative Innovation Center for Cardiovascular Disorders, Beijing Institute of Heart Lung and Blood Vessel DiseaseBeijingChina
| | - Han Guo
- Beijing An Zhen HospitalCapital Medical University, The Key Laboratory of Remodeling Cardiovascular Diseases, Ministry of Education; Collaborative Innovation Center for Cardiovascular Disorders, Beijing Institute of Heart Lung and Blood Vessel DiseaseBeijingChina
| | - Xinwei Li
- Beijing An Zhen HospitalCapital Medical University, The Key Laboratory of Remodeling Cardiovascular Diseases, Ministry of Education; Collaborative Innovation Center for Cardiovascular Disorders, Beijing Institute of Heart Lung and Blood Vessel DiseaseBeijingChina
| | - Yang Liu
- Beijing An Zhen HospitalCapital Medical University, The Key Laboratory of Remodeling Cardiovascular Diseases, Ministry of Education; Collaborative Innovation Center for Cardiovascular Disorders, Beijing Institute of Heart Lung and Blood Vessel DiseaseBeijingChina
| | - Xinxin Li
- Beijing An Zhen HospitalCapital Medical University, The Key Laboratory of Remodeling Cardiovascular Diseases, Ministry of Education; Collaborative Innovation Center for Cardiovascular Disorders, Beijing Institute of Heart Lung and Blood Vessel DiseaseBeijingChina
| | - Zhengshuo Cui
- Beijing An Zhen HospitalCapital Medical University, The Key Laboratory of Remodeling Cardiovascular Diseases, Ministry of Education; Collaborative Innovation Center for Cardiovascular Disorders, Beijing Institute of Heart Lung and Blood Vessel DiseaseBeijingChina
| | - Huijuan Ma
- Department of HypertensionBeijing An Zhen HospitalCapital Medical UniversityBeijingChina
| | - Jianxun He
- Beijing Anzhen Hospital Laboratory DepartmentBeijing Anzhen HospitalCapital Medical UniversityBeijingChina
| | - Zhechun Zeng
- Beijing An Zhen HospitalCapital Medical University, The Key Laboratory of Remodeling Cardiovascular Diseases, Ministry of Education; Collaborative Innovation Center for Cardiovascular Disorders, Beijing Institute of Heart Lung and Blood Vessel DiseaseBeijingChina
| | - Huina Zhang
- Beijing An Zhen HospitalCapital Medical University, The Key Laboratory of Remodeling Cardiovascular Diseases, Ministry of Education; Collaborative Innovation Center for Cardiovascular Disorders, Beijing Institute of Heart Lung and Blood Vessel DiseaseBeijingChina
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6
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Yu WW, Barrett JNP, Tong J, Lin MJ, Marohn M, Devlin JC, Herrera A, Remark J, Levine J, Liu PK, Fang V, Zellmer AM, Oldridge DA, Wherry EJ, Lin JR, Chen JY, Sorger P, Santagata S, Krueger JG, Ruggles KV, Wang F, Su C, Koralov SB, Wang J, Chiu ES, Lu CP. Skin immune-mesenchymal interplay within tertiary lymphoid structures promotes autoimmune pathogenesis in hidradenitis suppurativa. Immunity 2024; 57:2827-2842.e5. [PMID: 39662091 DOI: 10.1016/j.immuni.2024.11.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 09/04/2024] [Accepted: 11/08/2024] [Indexed: 12/13/2024]
Abstract
Hidradenitis suppurativa (HS) is a chronic, debilitating inflammatory skin disease characterized by keratinized epithelial tunnels that grow deeply into the dermis. Here, we examined the immune microenvironment within human HS lesions. Multi-omics profiling and multiplexed imaging identified tertiary lymphoid structures (TLSs) near HS tunnels. These TLSs were enriched with proliferative T cells, including follicular helper (Tfh), regulatory (Treg), and pathogenic T cells (IL17A+ and IFNG+), alongside extensive clonal expansion of plasma cells producing antibodies reactive to keratinocytes. HS fibroblasts express CXCL13 or CCL19 in response to immune cytokines. Using a microfluidic system to mimic TLS on a chip, we found that HS fibroblasts critically orchestrated lymphocyte aggregation via tumor necrosis factor alpha (TNF-α)-CXCL13 and TNF-α-CCL19 feedback loops with B and T cells, respectively; early TNF-α blockade suppressed aggregate initiation. Our findings provide insights into TLS formation in the skin, suggest therapeutic avenues for HS, and reveal mechanisms that may apply to other autoimmune settings, including Crohn's disease.
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Affiliation(s)
- Wei-Wen Yu
- The Hansjörg Wyss Department of Plastic Surgery, New York University Grossman School of Medicine, New York, NY, USA
| | - Joy N P Barrett
- The Hansjörg Wyss Department of Plastic Surgery, New York University Grossman School of Medicine, New York, NY, USA
| | - Jie Tong
- The Hansjörg Wyss Department of Plastic Surgery, New York University Grossman School of Medicine, New York, NY, USA
| | - Meng-Ju Lin
- The Hansjörg Wyss Department of Plastic Surgery, New York University Grossman School of Medicine, New York, NY, USA
| | - Meaghan Marohn
- The Hansjörg Wyss Department of Plastic Surgery, New York University Grossman School of Medicine, New York, NY, USA
| | - Joseph C Devlin
- Institute of Systems Genetics, New York University Grossman School of Medicine, New York, NY, USA; Vilcek Institute of Graduate Biomedical Sciences, New York University Grossman School of Medicine, New York, NY, USA
| | - Alberto Herrera
- Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA
| | - Juliana Remark
- The Hansjörg Wyss Department of Plastic Surgery, New York University Grossman School of Medicine, New York, NY, USA; Vilcek Institute of Graduate Biomedical Sciences, New York University Grossman School of Medicine, New York, NY, USA
| | - Jamie Levine
- The Hansjörg Wyss Department of Plastic Surgery, New York University Grossman School of Medicine, New York, NY, USA
| | - Pei-Kang Liu
- Department of Ophthalmology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Victoria Fang
- Institute for Immunology and Immune Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; The Colton Center for Autoimmunity at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Abigail M Zellmer
- Center for Computational and Genomic Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Derek A Oldridge
- Institute for Immunology and Immune Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Center for Computational and Genomic Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - E John Wherry
- Institute for Immunology and Immune Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; The Colton Center for Autoimmunity at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Jia-Ren Lin
- Laboratory of Systems Pharmacology, Department of Systems Biology, Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA
| | - Jia-Yun Chen
- Laboratory of Systems Pharmacology, Department of Systems Biology, Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA
| | - Peter Sorger
- Laboratory of Systems Pharmacology, Department of Systems Biology, Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA
| | - Sandro Santagata
- Laboratory of Systems Pharmacology, Department of Systems Biology, Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
| | - James G Krueger
- Laboratory of Investigative Dermatology, The Rockefeller University, New York, NY, USA
| | - Kelly V Ruggles
- Institute of Systems Genetics, New York University Grossman School of Medicine, New York, NY, USA; Division of Precision Medicine, Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA
| | - Fei Wang
- Department of Population Health Sciences, Weill Cornell Medicine, Cornell University, New York, NY, USA; Institute of Artificial Intelligence for Digital Health, Weill Cornell Medicine, Cornell University, New York, NY, USA
| | - Chang Su
- Department of Population Health Sciences, Weill Cornell Medicine, Cornell University, New York, NY, USA; Institute of Artificial Intelligence for Digital Health, Weill Cornell Medicine, Cornell University, New York, NY, USA
| | - Sergei B Koralov
- Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA
| | - Jun Wang
- Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA; The Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016, USA
| | - Ernest S Chiu
- The Hansjörg Wyss Department of Plastic Surgery, New York University Grossman School of Medicine, New York, NY, USA
| | - Catherine P Lu
- The Hansjörg Wyss Department of Plastic Surgery, New York University Grossman School of Medicine, New York, NY, USA; Department of Cell Biology, New York University Grossman School of Medicine, New York, NY, USA.
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7
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Feng Y, Cheng Z, Gao J, Huang T, Wang J, Tang Q, Pu K, Liu C. Revolutionizing prognostic predictions in colorectal cancer: Macrophage‑driven transcriptional insights from single‑cell RNA sequencing and gene co‑expression network analysis. Oncol Lett 2024; 28:587. [PMID: 39411205 PMCID: PMC11474140 DOI: 10.3892/ol.2024.14721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 08/23/2024] [Indexed: 10/19/2024] Open
Abstract
Tumor-associated macrophages have become important biomarkers for cancer diagnosis, prognosis and therapy. The dynamic changes in macrophage subpopulations significantly impact the outcomes of cancer immunotherapy. Hence, identifying additional macrophage-related biomarkers is essential for enhancing prognostic predictions in colorectal cancer (CRC) immunotherapy. CRC single-cell RNA sequencing (scRNA-seq) data was obtained from the Gene Expression Omnibus (GEO) database. The data were processed, normalized and clustered using the 'Seurat' package. Cell types within each cluster were annotated using the 'SingleR' package. Weighted gene co-expression network analysis identified modules corresponding to specific cell types. A non-negative matrix factorization algorithm was employed to segregate different clusters based on the selected module. Differentially expressed genes (DEGs) were identified across various clusters and a prognostic model was constructed using lasso regression and Cox regression analyses. The robustness of the model was validated using The Cancer Genome Atlas (TCGA) database and GEO microarrays. Additionally, the prognosis, immune characteristics and response to immune checkpoint inhibitor (ICI) therapy were individually analyzed. The scRNA-seq data from GSE200997, consisting of 23 samples, were analyzed. Dimensionality reduction and cluster identification allowed the isolation of the primary myeloid cell subpopulations. The macrophage-related brown module was identified, which was further divided into two clusters. Using the DEGs from these clusters, a prognostic model was developed, comprising five macrophage-related genes. The robustness of the model was confirmed using microarray datasets GSE17536, GSE38832 and GSE39582, as well as TCGA cohort. Patients classified as high-risk by the present model exhibited poorer survival rates, lower tumor mutation burden, reduced microsatellite instability, lower tumor purity, more severe tumor immune dysfunction and exclusion, and less benefit from ICIs therapy compared with low-risk patients. The present prognostic model shows promise as a biomarker for risk stratification and predicting therapeutic efficacy in patients with CRC. However, further well-designed prospective studies are necessary to validate the findings.
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Affiliation(s)
- Yang Feng
- Key Laboratory of Surgical Critical Care and Life Support, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi 710061, P.R. China
- Department of Neurosurgery, Xi'an No. 3 Hospital, The Affiliated Hospital of Northwest University, Xi'an, Shaanxi 710018, P.R. China
| | - Zhuo Cheng
- Department of Gastroenterology, Dazhou Central Hospital, Dazhou, Sichuan 635000, P.R. China
| | - Jingyuan Gao
- Department of Immunology, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi 712046, P.R. China
| | - Tao Huang
- Department of Gastroenterology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Jun Wang
- Department of Gastroenterology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Qian Tang
- Statesboro Office, Southeast Medical Group, Atlanta, GA 30022, USA
| | - Ke Pu
- Department of Gastroenterology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Chang Liu
- Key Laboratory of Surgical Critical Care and Life Support, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi 710061, P.R. China
- Department of Hepatobiliary Surgery and Liver Transplantation, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
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Li C, Yuan H, Chen J, Shang K, He H. The oncogenic functions of SPARCL1 in bladder cancer. J Cell Mol Med 2024; 28:e70196. [PMID: 39548034 PMCID: PMC11567778 DOI: 10.1111/jcmm.70196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Revised: 10/14/2024] [Accepted: 10/27/2024] [Indexed: 11/17/2024] Open
Abstract
Secreted protein, acidic and rich in cysteine-like 1 (SPARCL1) belongs to the SPARC family of matricellular proteins. However, underlying functions of SPARCL1 in bladder cancer (BCa) remain understudied. We performed an integrated search for the expression patterns of SPARCL1 in relation to various clinicopathological features of BCa. We then carried out Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and gene set enrichment analysis (GSEA). Furthermore, we investigated the correlations between SPARCL1 and immunological features, such as tumour mutation burden (TMB), immune activation processes, immune checkpoint expression, tumour immune dysfunction and exclusion (TIDE) scores, and chemotherapeutic sensitivity in BCa. Our analysis revealed that SPARCL1 was downregulated across multiple cancers. In BCa, elevated SPARCL1 was linked with advanced histopathologic stage, higher T and N stage, and poorer prognosis in the clinical cohort. In vitro experiments demonstrated that increased SPARCL1 expression inhibited cell proliferation, migration, and invasion. Additionally, highly expressed SPARCL1 was linked to elevated immune, stromal and ESTIMATE scores, as well as an increase in naive B cells, M2 macrophages, and resting mast cells. We observed a moderate correlation between SPARCL1 expression and CD163, VSIG4 and MS4A4A, which are markers of M2 macrophages. Furthermore, SPARCL1 expression was positively related to TMB, immune activation processes, TIDE scores, immune checkpoint expression, and chemotherapeutic sensitivity in BCa. Our study highlights the potential involvement of SPARCL1 in macrophage recruitment and polarization and suggests its utility as a biomarker for prognosis in BCa.
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Affiliation(s)
- Changjiu Li
- Department of Urology, Affiliated Hangzhou First People's HospitalWestlake University School of MedicineHangzhouChina
| | - Hui Yuan
- The Fourth Clinical Medical CollegeZhejiang Chinese Medical UniversityHangzhouChina
- Department of UrologyNinghai First HospitalNingbo
| | - Jun Chen
- The Fourth Clinical Medical CollegeZhejiang Chinese Medical UniversityHangzhouChina
| | - Kun Shang
- The Fourth Clinical Medical CollegeZhejiang Chinese Medical UniversityHangzhouChina
| | - Huadong He
- Department of Urology, Affiliated Hangzhou First People's HospitalWestlake University School of MedicineHangzhouChina
- The Fourth Clinical Medical CollegeZhejiang Chinese Medical UniversityHangzhouChina
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9
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Dorner H, Stolzer I, Mattner J, Kaminski S, Leistl S, Edrich LM, Schwendner R, Hobauer J, Sebald A, Leikam S, Gonzalez Acera M, Düll M, Lang R, Seidel G, Seitz T, Hellerbrand C, Fuhrmann G, Distler U, Tenzer S, Eichhorn P, Vieth M, Schramm C, Arnold P, Becker C, Weidinger C, Siegmund B, Atreya R, Leppkes M, Naschberger E, Sampaziotis F, Dietrich P, Rauh M, Wirtz S, Kremer AE, Neurath MF, Günther C. Gut Pathobiont-Derived Outer Membrane Vesicles Drive Liver Inflammation and Fibrosis in Primary Sclerosing Cholangitis-Associated Inflammatory Bowel Disease. Gastroenterology 2024; 167:1183-1197.e16. [PMID: 38992449 DOI: 10.1053/j.gastro.2024.06.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 06/21/2024] [Accepted: 06/24/2024] [Indexed: 07/13/2024]
Abstract
BACKGROUND & AIMS Primary sclerosing cholangitis (PSC), often associated with inflammatory bowel disease (IBD), presents a multifactorial etiology involving genetic, immunologic, and environmental factors. Gut dysbiosis and bacterial translocation have been implicated in PSC-IBD, yet the precise mechanisms underlying their pathogenesis remain elusive. Here, we describe the role of gut pathobionts in promoting liver inflammation and fibrosis due to the release of bacterial outer membrane vesicles (OMVs). METHODS Preclinical mouse models in addition to ductal organoids were used to acquire mechanistic data. A proof-of-concept study including serum and liver biopsies of a patient cohort of PSC (n = 22), PSC-IBD (n = 45), and control individuals (n = 27) was performed to detect OMVs in the systemic circulation and liver. RESULTS In both preclinical model systems and in patients with PSC-IBD, the translocation of OMVs to the liver correlated with enhanced bacterial sensing and accumulation of the NLRP3 inflammasome. Using ductal organoids, we were able to precisely attribute the pro-inflammatory and pro-fibrogenic properties of OMVs to signaling pathways dependent on Toll-like receptor 4 and NLRP3-gasdermin-D. The immunostimulatory potential of OMVs could be confirmed in macrophages and hepatic stellate cells. Furthermore, when we administered gut pathobiont-derived OMVs to Mdr2-/- mice, we observed a significant enhancement in liver inflammation and fibrosis. In a translational approach, we substantiated the presence of OMVs in the systemic circulation and hepatic regions of severe fibrosis using a PSC-IBD patient cohort. CONCLUSIONS This study demonstrates the contribution of gut pathobionts in releasing OMVs that traverse the mucosal barrier and, thus, promote liver inflammation and fibrosis in PSC-IBD. OMVs might represent a critical new environmental factor that interacts with other disease factors to cause inflammation and thus define potential new targets for fibrosis therapy.
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Affiliation(s)
- Heidrun Dorner
- Department of Medicine 1, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Iris Stolzer
- Department of Medicine 1, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Jochen Mattner
- Institute of Clinical Microbiology, Immunology and Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Friedrich-Alexander-Universität Erlangen-Nürnberg Profile Center Immunomedicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Sophie Kaminski
- Department of Medicine 1, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Sofia Leistl
- Department of Medicine 1, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Lisa-Maria Edrich
- Department of Medicine 1, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Raphael Schwendner
- Department of Medicine 1, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Julia Hobauer
- Department of Medicine 1, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Adrian Sebald
- Department of Medicine 1, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Stefanie Leikam
- Department of Medicine 1, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Miguel Gonzalez Acera
- Department of Medicine 1, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Miriam Düll
- Department of Medicine 1, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Roland Lang
- Institute of Clinical Microbiology, Immunology and Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Friedrich-Alexander-Universität Erlangen-Nürnberg Profile Center Immunomedicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Gerald Seidel
- Microbiology, Department of Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Tatjana Seitz
- Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Claus Hellerbrand
- Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Gregor Fuhrmann
- Department of Biology, Pharmaceutical Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Ute Distler
- Institute of Immunology, University Medical Center of the Johannes-Gutenberg University, Mainz, Germany
| | - Stefan Tenzer
- Institute of Immunology, University Medical Center of the Johannes-Gutenberg University, Mainz, Germany
| | - Phillip Eichhorn
- Institute of Pathology, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Michael Vieth
- Institute of Pathology, Klinikum Bayreuth, Friedrich-Alexander-Universität Erlangen-Nürnberg, Bayreuth, Germany
| | - Christoph Schramm
- Department of Medicine, Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Philipp Arnold
- Institute of Functional and Clinical Anatomy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Christoph Becker
- Department of Medicine 1, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Friedrich-Alexander-Universität Erlangen-Nürnberg Profile Center Immunomedicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Deutsches Zentrum Immuntherapie, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Carl Weidinger
- Division of Gastroenterology, Infectiology and Rheumatology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Britta Siegmund
- Division of Gastroenterology, Infectiology and Rheumatology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Raja Atreya
- Department of Medicine 1, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Friedrich-Alexander-Universität Erlangen-Nürnberg Profile Center Immunomedicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Deutsches Zentrum Immuntherapie, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Moritz Leppkes
- Department of Medicine 1, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Deutsches Zentrum Immuntherapie, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Elisabeth Naschberger
- Division of Molecular and Experimental Surgery, Department of Surgery, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Fotios Sampaziotis
- Wellcome-Medical Research Council Cambridge Stem Cell Institute, Cambridge, United Kingdom; Cambridge Liver Unit, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, United Kingdom; Department of Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Peter Dietrich
- Department of Medicine 1, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Manfred Rauh
- Research Laboratory, Division of Pediatrics, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Stefan Wirtz
- Department of Medicine 1, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Friedrich-Alexander-Universität Erlangen-Nürnberg Profile Center Immunomedicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Deutsches Zentrum Immuntherapie, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Andreas E Kremer
- Department of Medicine 1, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Deutsches Zentrum Immuntherapie, Universitätsklinikum Erlangen, Erlangen, Germany; Department of Gastroenterology and Hepatology, University Hospital Zürich, University of Zürich, Zürich, Switzerland
| | - Markus F Neurath
- Department of Medicine 1, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Friedrich-Alexander-Universität Erlangen-Nürnberg Profile Center Immunomedicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Deutsches Zentrum Immuntherapie, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Claudia Günther
- Department of Medicine 1, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Friedrich-Alexander-Universität Erlangen-Nürnberg Profile Center Immunomedicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Deutsches Zentrum Immuntherapie, Universitätsklinikum Erlangen, Erlangen, Germany.
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10
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Zhao G, Gentile ME, Xue L, Cosgriff CV, Weiner AI, Adams-Tzivelekidis S, Wong J, Li X, Kass-Gergi S, Holcomb NP, Basal MC, Stewart KM, Planer JD, Cantu E, Christie JD, Crespo MM, Mitchell MJ, Meyer NJ, Vaughan AE. Vascular endothelial-derived SPARCL1 exacerbates viral pneumonia through pro-inflammatory macrophage activation. Nat Commun 2024; 15:4235. [PMID: 38762489 PMCID: PMC11102455 DOI: 10.1038/s41467-024-48589-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 05/06/2024] [Indexed: 05/20/2024] Open
Abstract
Inflammation induced by lung infection is a double-edged sword, moderating both anti-viral and immune pathogenesis effects; the mechanism of the latter is not fully understood. Previous studies suggest the vasculature is involved in tissue injury. Here, we report that expression of Sparcl1, a secreted matricellular protein, is upregulated in pulmonary capillary endothelial cells (EC) during influenza-induced lung injury. Endothelial overexpression of SPARCL1 promotes detrimental lung inflammation, with SPARCL1 inducing 'M1-like' macrophages and related pro-inflammatory cytokines, while SPARCL1 deletion alleviates these effects. Mechanistically, SPARCL1 functions through TLR4 on macrophages in vitro, while TLR4 inhibition in vivo ameliorates excessive inflammation caused by endothelial Sparcl1 overexpression. Finally, SPARCL1 expression is increased in lung ECs from COVID-19 patients when compared with healthy donors, while fatal COVID-19 correlates with higher circulating SPARCL1 protein levels in the plasma. Our results thus implicate SPARCL1 as a potential prognosis biomarker for deadly COVID-19 pneumonia and as a therapeutic target for taming hyperinflammation in pneumonia.
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Affiliation(s)
- Gan Zhao
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
- Penn-CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA.
| | - Maria E Gentile
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Penn-CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Lulu Xue
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Christopher V Cosgriff
- Pulmonary and Critical Care Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA
| | - Aaron I Weiner
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Penn-CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Stephanie Adams-Tzivelekidis
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Penn-CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Joanna Wong
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Penn-CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Xinyuan Li
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Penn-CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Sara Kass-Gergi
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Penn-CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Division of Pulmonary, Allergy and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Nicolas P Holcomb
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Penn-CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Maria C Basal
- Penn-CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Division of Pulmonary, Allergy and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Kathleen M Stewart
- Penn-CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Division of Pulmonary, Allergy and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Joseph D Planer
- Penn-CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Division of Pulmonary, Allergy and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Edward Cantu
- Penn-CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Division of Cardiovascular Surgery, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Jason D Christie
- Penn-CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Division of Pulmonary, Allergy and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Maria M Crespo
- Penn-CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Division of Pulmonary, Allergy and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Michael J Mitchell
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Nuala J Meyer
- Penn-CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Division of Pulmonary, Allergy and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Andrew E Vaughan
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
- Penn-CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA.
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11
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Miao Y, Wu S, Gong Z, Chen Y, Xue F, Liu K, Zou J, Feng Y, Li G. SPARCL1 promotes chondrocytes extracellular matrix degradation and inflammation in osteoarthritis via TNF/NF-κB pathway. J Orthop Translat 2024; 46:116-128. [PMID: 38867741 PMCID: PMC11167206 DOI: 10.1016/j.jot.2024.02.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 11/27/2023] [Accepted: 02/29/2024] [Indexed: 06/14/2024] Open
Abstract
Objectives SPARCL1 is a matricellular protein that mediates the cell-matrix interactions and participates in physiological processes such as cell adhesion, differentiation and proliferation. However, its role in chondrocyte and osteoarthritis (OA) progression has not been fully characterized. We aimed to evaluate the effects of SPARCL1 on OA through in vitro and in vivo experiments. Methods Expression of SPARCL1 was examined in 55 paired human OA samples. Effects of Sparcl1 on chondrocytes were identified in vitro. Intra-articular injection was performed in an anterior cruciate ligament transection (ACLT) mouse model. Alterations of SPARCL1-mediated signaling pathway were identified by RNA-seq analysis. qPCR and western-blot were used to demonstrate the potential signaling pathway. Results SPARCL1 expression in the OA cartilage was increased compared with undamaged cartilage. Recombinant Sparcl1 protein induced extracellular matrix degradation in chondrocytes. Furthermore, intra-articular injection of recombinant Sparcl1 protein in ACLT mice could promote OA pathogenesis. Mechanistically, Sparcl1 activated TNF/NF-κB pathway and consequently led to increased transcription of inflammatory factors and catabolism genes of cartilage, which could be reversed by NF-κB inhibitor BAY 11-7082. Conclusion SPARCL1 could promote extracellular matrix degradation and inflammatory response to accelerate OA progression via TNF/NF-κB pathway. The translational potential of this article The current research could help to gain further insights into the underlying molecular mechanism in OA development, and provides a biological rationale for the use of SPARCL1 as a potential therapeutic target of OA.
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Affiliation(s)
- Yu Miao
- Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No.600, Yishan Road, Shanghai, 200233, China
- Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Shenghui Wu
- Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No.600, Yishan Road, Shanghai, 200233, China
- Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Ziling Gong
- Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No.600, Yishan Road, Shanghai, 200233, China
- Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Yiwei Chen
- Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No.600, Yishan Road, Shanghai, 200233, China
- Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Feng Xue
- Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No.600, Yishan Road, Shanghai, 200233, China
- Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Kexin Liu
- Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No.600, Yishan Road, Shanghai, 200233, China
- Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Jian Zou
- Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No.600, Yishan Road, Shanghai, 200233, China
| | - Yong Feng
- Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No.600, Yishan Road, Shanghai, 200233, China
- Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Guangyi Li
- Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No.600, Yishan Road, Shanghai, 200233, China
- Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
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12
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Kondo Y, Li Y, Okajima T. Efficient Escorting Strategy for Aggregation-Prone Notch EGF Repeats with Sparcl1. Molecules 2024; 29:1031. [PMID: 38474544 DOI: 10.3390/molecules29051031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 02/26/2024] [Accepted: 02/26/2024] [Indexed: 03/14/2024] Open
Abstract
Epidermal growth factor (EGF) repeats are present in various proteins and form well-defined structures with three disulfide bonds. One representative protein is the Notch receptor. Each EGF repeat contains unique atypical O-linked glycans, such as O-linked N-acetylglucosamine (O-GlcNAc). To generate a monoclonal antibody against the O-GlcNAc moiety in mouse Notch1, we expressed the recombinant C-terminal His6-tagged Notch1 EGF14-15 protein in HEK293T cells to prepare the immunogen. Most of the proteins were not secreted and showed higher molecular weight ladders in the cell lysate, suggesting protein aggregation. To overcome this issue, we fused Sparcl1 as an extracellular escorting tag to the N-terminus of Notch1 EGF14-15. The fusion protein was efficiently secreted extracellularly without protein aggregates in the lysates. Following PreScission protease treatment, Notch1 EGF14-15 was efficiently released from the escorting tag. Notch1 EGF14-15 prepared using this method was indeed O-GlcNAcylated. The optimal length of the escorting tag was determined by generating deletion mutants to improve the extracellular secretion of EGF14-15. Hence, a large amount of EGF14-15 was successfully prepared from the culture supernatant of HEK293T cells, which were otherwise prone to aggregation.
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Affiliation(s)
- Yuji Kondo
- Department of Molecular Biochemistry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
- Institute for Glyco-core Research (iGCORE), Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan
| | - Yuxin Li
- Department of Molecular Biochemistry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
| | - Tetsuya Okajima
- Department of Molecular Biochemistry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
- Institute for Glyco-core Research (iGCORE), Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan
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13
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Jacobsen A, Siebler J, Grützmann R, Stürzl M, Naschberger E. Blood Vessel-Targeted Therapy in Colorectal Cancer: Current Strategies and Future Perspectives. Cancers (Basel) 2024; 16:890. [PMID: 38473252 DOI: 10.3390/cancers16050890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 02/06/2024] [Accepted: 02/10/2024] [Indexed: 03/14/2024] Open
Abstract
The vasculature is a key player and regulatory component in the multicellular microenvironment of solid tumors and, consequently, a therapeutic target. In colorectal carcinoma (CRC), antiangiogenic treatment was approved almost 20 years ago, but there are still no valid predictors of response. In addition, treatment resistance has become a problem. Vascular heterogeneity and plasticity due to species-, organ-, and milieu-dependent phenotypic and functional differences of blood vascular cells reduced the hope of being able to apply a standard approach of antiangiogenic therapy to all patients. In addition, the pathological vasculature in CRC is characterized by heterogeneous perfusion, impaired barrier function, immunosuppressive endothelial cell anergy, and metabolic competition-induced microenvironmental stress. Only recently, angiocrine proteins have been identified that are specifically released from vascular cells and can regulate tumor initiation and progression in an autocrine and paracrine manner. In this review, we summarize the history and current strategies for applying antiangiogenic treatment and discuss the associated challenges and opportunities, including normalizing the tumor vasculature, modulating milieu-dependent vascular heterogeneity, and targeting functions of angiocrine proteins. These new strategies could open perspectives for future vascular-targeted and patient-tailored therapy selection in CRC.
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Affiliation(s)
- Anne Jacobsen
- Division of Molecular and Experimental Surgery, Translational Research Center, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Kussmaulallee 12, D-91054 Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), D-91054 Erlangen, Germany
- Department of General and Visceral Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), D-91054 Erlangen, Germany
| | - Jürgen Siebler
- Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), D-91054 Erlangen, Germany
- Department of Medicine 1-Gastroenterology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), D-91054 Erlangen, Germany
| | - Robert Grützmann
- Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), D-91054 Erlangen, Germany
- Department of General and Visceral Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), D-91054 Erlangen, Germany
| | - Michael Stürzl
- Division of Molecular and Experimental Surgery, Translational Research Center, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Kussmaulallee 12, D-91054 Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), D-91054 Erlangen, Germany
| | - Elisabeth Naschberger
- Division of Molecular and Experimental Surgery, Translational Research Center, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Kussmaulallee 12, D-91054 Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), D-91054 Erlangen, Germany
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14
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Naschberger E, Fuchs M, Dickel N, Kunz M, Popp B, Anchang CG, Demmler R, Lyu Y, Uebe S, Ekici AB, Geppert CI, Hartmann A, Flierl C, Petter K, Gass T, Völkl S, Scharl M, Ramming A, Günther C, Merkel S, Schellerer VS, Stürzl M. Tumor microenvironment-dependent epigenetic imprinting in the vasculature predicts colon cancer outcome. Cancer Commun (Lond) 2023; 43:1280-1285. [PMID: 37859581 PMCID: PMC10631479 DOI: 10.1002/cac2.12489] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 09/05/2023] [Accepted: 09/20/2023] [Indexed: 10/21/2023] Open
Affiliation(s)
- Elisabeth Naschberger
- Division of Molecular and Experimental SurgeryTranslational Research CenterUniversitätsklinikum ErlangenFriedrich‐Alexander‐Universität Erlangen‐Nürnberg (FAU)ErlangenBavariaGermany
- Comprehensive Cancer Center Erlangen‐EMN (CCC ER‐EMN)ErlangenBavariaGermany
| | - Maximilian Fuchs
- Chair of Medical InformaticsFriedrich‐Alexander‐Universität Erlangen‐Nürnberg (FAU)ErlangenBavariaGermany
- Fraunhofer Institute of Toxicology and Experimental MedicineLower saxonyHannoverGermany
| | - Nicholas Dickel
- Chair of Medical InformaticsFriedrich‐Alexander‐Universität Erlangen‐Nürnberg (FAU)ErlangenBavariaGermany
| | - Meik Kunz
- Chair of Medical InformaticsFriedrich‐Alexander‐Universität Erlangen‐Nürnberg (FAU)ErlangenBavariaGermany
- Fraunhofer Institute of Toxicology and Experimental MedicineLower saxonyHannoverGermany
| | - Bernt Popp
- Institute of Human GeneticsUniversitätsklinikum ErlangenFriedrich‐Alexander‐Universität Erlangen‐Nürnberg (FAU)ErlangenBavariaGermany
| | - Charles Gwellem Anchang
- Department of Medicine 3Universitätsklinikum ErlangenFriedrich‐Alexander‐Universität Erlangen‐Nürnberg (FAU)ErlangenBavariaGermany
| | - Richard Demmler
- Division of Molecular and Experimental SurgeryTranslational Research CenterUniversitätsklinikum ErlangenFriedrich‐Alexander‐Universität Erlangen‐Nürnberg (FAU)ErlangenBavariaGermany
- Comprehensive Cancer Center Erlangen‐EMN (CCC ER‐EMN)ErlangenBavariaGermany
| | - Yanmin Lyu
- Division of Molecular and Experimental SurgeryTranslational Research CenterUniversitätsklinikum ErlangenFriedrich‐Alexander‐Universität Erlangen‐Nürnberg (FAU)ErlangenBavariaGermany
- Comprehensive Cancer Center Erlangen‐EMN (CCC ER‐EMN)ErlangenBavariaGermany
| | - Steffen Uebe
- Institute of Human GeneticsUniversitätsklinikum ErlangenFriedrich‐Alexander‐Universität Erlangen‐Nürnberg (FAU)ErlangenBavariaGermany
| | - Arif Bülent Ekici
- Institute of Human GeneticsUniversitätsklinikum ErlangenFriedrich‐Alexander‐Universität Erlangen‐Nürnberg (FAU)ErlangenBavariaGermany
| | - Carol Immanuel Geppert
- Comprehensive Cancer Center Erlangen‐EMN (CCC ER‐EMN)ErlangenBavariaGermany
- Institute of PathologyUniversitätsklinikum ErlangenFriedrich‐Alexander‐Universität Erlangen‐Nürnberg (FAU)ErlangenBavariaGermany
| | - Arndt Hartmann
- Comprehensive Cancer Center Erlangen‐EMN (CCC ER‐EMN)ErlangenBavariaGermany
- Institute of PathologyUniversitätsklinikum ErlangenFriedrich‐Alexander‐Universität Erlangen‐Nürnberg (FAU)ErlangenBavariaGermany
| | - Christian Flierl
- Division of Molecular and Experimental SurgeryTranslational Research CenterUniversitätsklinikum ErlangenFriedrich‐Alexander‐Universität Erlangen‐Nürnberg (FAU)ErlangenBavariaGermany
| | - Katja Petter
- Division of Molecular and Experimental SurgeryTranslational Research CenterUniversitätsklinikum ErlangenFriedrich‐Alexander‐Universität Erlangen‐Nürnberg (FAU)ErlangenBavariaGermany
| | - Tobias Gass
- Division of Molecular and Experimental SurgeryTranslational Research CenterUniversitätsklinikum ErlangenFriedrich‐Alexander‐Universität Erlangen‐Nürnberg (FAU)ErlangenBavariaGermany
| | - Simon Völkl
- Department of Internal Medicine 5 – Hematology and OncologyUniversitätsklinikum ErlangenFriedrich‐Alexander‐Universität Erlangen‐Nürnberg (FAU)ErlangenBavariaGermany
| | - Michael Scharl
- Department of Gastroenterology and HepatologyUniversity Hospital ZurichUniversity of ZurichCanton ZurichZurichSwitzerland
| | - Andreas Ramming
- Department of Medicine 3Universitätsklinikum ErlangenFriedrich‐Alexander‐Universität Erlangen‐Nürnberg (FAU)ErlangenBavariaGermany
| | - Claudia Günther
- Department of Medicine 1Universitätsklinikum ErlangenFriedrich‐Alexander‐Universität Erlangen‐Nürnberg (FAU)ErlangenBavariaGermany
| | - Susanne Merkel
- Comprehensive Cancer Center Erlangen‐EMN (CCC ER‐EMN)ErlangenBavariaGermany
- Department of SurgeryUniversitätsklinikum ErlangenFriedrich‐Alexander‐Universität Erlangen‐Nürnberg (FAU)ErlangenBavariaGermany
| | - Vera Simone Schellerer
- Comprehensive Cancer Center Erlangen‐EMN (CCC ER‐EMN)ErlangenBavariaGermany
- Department of SurgeryUniversitätsklinikum ErlangenFriedrich‐Alexander‐Universität Erlangen‐Nürnberg (FAU)ErlangenBavariaGermany
| | - Michael Stürzl
- Division of Molecular and Experimental SurgeryTranslational Research CenterUniversitätsklinikum ErlangenFriedrich‐Alexander‐Universität Erlangen‐Nürnberg (FAU)ErlangenBavariaGermany
- Comprehensive Cancer Center Erlangen‐EMN (CCC ER‐EMN)ErlangenBavariaGermany
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15
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Gao Q, Zhan Y, Sun L, Zhu W. Cancer Stem Cells and the Tumor Microenvironment in Tumor Drug Resistance. Stem Cell Rev Rep 2023; 19:2141-2154. [PMID: 37477773 DOI: 10.1007/s12015-023-10593-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/11/2023] [Indexed: 07/22/2023]
Abstract
Although there has been some progress in the efficacy of anti-cancer drugs, drug resistance remains challenging. Cancer stem cells (CSCs) are self-renewing and differentiate into cancer tissues with tumor heterogeneity. CSCs are associated with the progression of breast, colon, and lung cancers. Hence, recent studies have focused on the role of CSCs in resistance to anti-cancer drugs. Increasing evidence suggests that CSCs interact with components of the tumor microenvironment (TME), such as vascular and immune cells, as well as various cytokines, and are regulated by multiple signaling pathways, thereby promoting drug resistance in various cancers. Therefore, it is important to clarify the mechanisms underlying the crosstalk between CSCs and the TME for the development of targeted anti-cancer therapies.
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Affiliation(s)
- Qiuzhi Gao
- School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, Jiangsu, 212013, China
| | - Yixiang Zhan
- School of Medicine, Nankai University, Tianjin, 300071, China
| | - Li Sun
- Department of Clinical Laboratory, Affiliated Kunshan Hospital of Jiangsu University, Suzhou, Jiangsu, 215300, China
| | - Wei Zhu
- School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, Jiangsu, 212013, China.
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16
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Xu X, Xie J, Ling R, Ouyang S, Xiong G, Lu Y, Yun B, Zhang M, Wang W, Liu X, Chen D, Wang C. Single-cell transcriptomic analysis uncovers the origin and intratumoral heterogeneity of parotid pleomorphic adenoma. Int J Oral Sci 2023; 15:38. [PMID: 37679344 PMCID: PMC10484943 DOI: 10.1038/s41368-023-00243-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 08/16/2023] [Accepted: 08/16/2023] [Indexed: 09/09/2023] Open
Abstract
Pleomorphic adenoma (PA) is the most common benign tumour in the salivary gland and has high morphological complexity. However, the origin and intratumoral heterogeneity of PA are largely unknown. Here, we constructed a comprehensive atlas of PA at single-cell resolution and showed that PA exhibited five tumour subpopulations, three recapitulating the epithelial states of the normal parotid gland, and two PA-specific epithelial cell (PASE) populations unique to tumours. Then, six subgroups of PASE cells were identified, which varied in epithelium, bone, immune, metabolism, stemness and cell cycle signatures. Moreover, we revealed that CD36+ myoepithelial cells were the tumour-initiating cells (TICs) in PA, and were dominated by the PI3K-AKT pathway. Targeting the PI3K-AKT pathway significantly inhibited CD36+ myoepithelial cell-derived tumour spheres and the growth of PA organoids. Our results provide new insights into the diversity and origin of PA, offering an important clinical implication for targeting the PI3K-AKT signalling pathway in PA treatment.
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Affiliation(s)
- Xiuyun Xu
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, China
- Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Jiaxiang Xie
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, China
- Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Rongsong Ling
- Institute for Advanced Study, Shenzhen University, Shenzhen, China
| | - Shengqi Ouyang
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, China
- Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Gan Xiong
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, China
- Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Yanwen Lu
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, China
- Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Bokai Yun
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, China
- Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Ming Zhang
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, China
- Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Wenjin Wang
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, China
- Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Xiqiang Liu
- Department of Oral and Maxillofacial Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Demeng Chen
- Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
| | - Cheng Wang
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China.
- Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, China.
- Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China.
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17
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Naschberger E, Flierl C, Huang J, Erkert L, Gamez-Belmonte R, Gonzalez-Acera M, Bober M, Mehnert M, Becker C, Schellerer VS, Britzen-Laurent N, Stürzl M. Analysis of the interferon-γ-induced secretome of intestinal endothelial cells: putative impact on epithelial barrier dysfunction in IBD. Front Cell Dev Biol 2023; 11:1213383. [PMID: 37645250 PMCID: PMC10460912 DOI: 10.3389/fcell.2023.1213383] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 07/31/2023] [Indexed: 08/31/2023] Open
Abstract
The development of inflammatory bowel diseases (IBD) involves the breakdown of two barriers: the epithelial barrier and the gut-vascular barrier (GVB). The destabilization of each barrier can promote initiation and progression of the disease. Interestingly, first evidence is available that both barriers are communicating through secreted factors that may accordingly serve as targets for therapeutic modulation of barrier functions. Interferon (IFN)-γ is among the major pathogenesis factors in IBD and can severely impair both barriers. In order to identify factors transmitting signals from the GVB to the epithelial cell barrier, we analyzed the secretome of IFN-γ-treated human intestinal endothelial cells (HIEC). To this goal, HIEC were isolated in high purity from normal colon tissues. HIEC were either untreated or stimulated with IFN-γ (10 U/mL). After 48 h, conditioned media (CM) were harvested and subjected to comparative hyper reaction monitoring mass spectrometry (HRM™ MS). In total, 1,084 human proteins were detected in the HIEC-CM. Among these, 43 proteins were present in significantly different concentrations between the CM of IFN-γ- and control-stimulated HIEC. Several of these proteins were also differentially expressed in various murine colitis models as compared to healthy animals supporting the relevance of these proteins secreted by inflammatory activated HIEC in the inter-barrier communication in IBD. The angiocrine pathogenic impact of these differentially secreted HIEC proteins on the epithelial cell barrier and their perspectives as targets to treat IBD by modulation of trans-barrier communication is discussed in detail.
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Affiliation(s)
- Elisabeth Naschberger
- Division of Molecular and Experimental Surgery, Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Christian Flierl
- Division of Molecular and Experimental Surgery, Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Jinghao Huang
- Division of Molecular and Experimental Surgery, Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Lena Erkert
- Department of Medicine I, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Reyes Gamez-Belmonte
- Department of Medicine I, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Miguel Gonzalez-Acera
- Department of Medicine I, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | | | | | - Christoph Becker
- Department of Medicine I, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Vera S. Schellerer
- Department of Pediatric Surgery, University Medicine Greifswald, Greifswald, Germany
| | - Nathalie Britzen-Laurent
- Division of Surgical Research, Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Michael Stürzl
- Division of Molecular and Experimental Surgery, Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN, Universitätsklinikum Erlangen, Erlangen, Germany
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18
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Taketomi T, Tsuruta F. Mutations in Hevin/Sparcl1 and risk of autism spectrum disorder. Neural Regen Res 2023; 18:1499-1500. [PMID: 36571352 PMCID: PMC10075111 DOI: 10.4103/1673-5374.361543] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Affiliation(s)
- Takumi Taketomi
- Ph.D. Program in Human Biology, School of Integrative and Global Majors, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Fuminori Tsuruta
- Ph.D. Program in Human Biology, School of Integrative and Global Majors; Master's and Doctoral Programs in Biology, Faculty of Life and Environmental Sciences; Ph.D. Program in Humanics, School of Integrative and Global Majors; Master's and Doctoral Program in Neuroscience, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
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19
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Khan AH, Chowers I, Lotery AJ. Beyond the Complement Cascade: Insights into Systemic Immunosenescence and Inflammaging in Age-Related Macular Degeneration and Current Barriers to Treatment. Cells 2023; 12:1708. [PMID: 37443742 PMCID: PMC10340338 DOI: 10.3390/cells12131708] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Revised: 06/22/2023] [Accepted: 06/22/2023] [Indexed: 07/15/2023] Open
Abstract
Landmark genetic studies have revealed the effect of complement biology and its regulation on the pathogenesis of age-related macular degeneration (AMD). Limited phase 3 clinical trial data showing a benefit of complement inhibition in AMD raises the prospect of more complex mediators at play. Substantial evidence supports the role of para-inflammation in maintaining homeostasis in the retina and choroid. With increasing age, a decline in immune system regulation, known as immunosenescence, has been shown to alter the equilibrium maintained by para-inflammation. The altered equilibrium results in chronic, sterile inflammation with aging, termed 'inflammaging', including in the retina and choroid. The chronic inflammatory state in AMD is complex, with contributions from cells of the innate and adaptive branches of the immune system, sometimes with overlapping features, and the interaction of their secretory products with retinal cells such as microglia and retinal pigment epithelium (RPE), extracellular matrix and choroidal vascular endothelial cells. In this review, the chronic inflammatory state in AMD will be explored by immune cell type, with a discussion of factors that will need to be overcome in the development of curative therapies.
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Affiliation(s)
- Adnan H. Khan
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK
- Southampton Eye Unit, University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK
| | - Itay Chowers
- Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel
- Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91121, Israel
| | - Andrew J. Lotery
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK
- Southampton Eye Unit, University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK
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20
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Zhao G, Gentile ME, Xue L, Cosgriff CV, Weiner AI, Adams-Tzivelekidis S, Wong J, Li X, Kass-Gergi S, Holcomb NP, Basal MC, Stewart KM, Planer JD, Cantu E, Christie JD, Crespo MM, Mitchell MJ, Meyer NJ, Vaughan AE. Vascular Endothelial-derived SPARCL1 Exacerbates Viral Pneumonia Through Pro-Inflammatory Macrophage Activation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.25.541966. [PMID: 37292817 PMCID: PMC10245987 DOI: 10.1101/2023.05.25.541966] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Inflammation upon infectious lung injury is a double-edged sword: while tissue-infiltrating immune cells and cytokines are necessary to control infection, these same factors often aggravate injury. Full appreciation of both the sources and targets of inflammatory mediators is required to facilitate strategies to maintain antimicrobial effects while minimizing off-target epithelial and endothelial damage. Recognizing that the vasculature is centrally involved in tissue responses to injury and infection, we observed that pulmonary capillary endothelial cells (ECs) exhibit dramatic transcriptomic changes upon influenza injury punctuated by profound upregulation of Sparcl1 . Endothelial deletion and overexpression of SPARCL1 implicated this secreted matricellular protein in driving key pathophysiologic symptoms of pneumonia, which we demonstrate result from its effects on macrophage polarization. SPARCL1 induces a shift to a pro-inflammatory "M1-like" phenotype (CD86 + CD206 - ), thereby increasing associated cytokine levels. Mechanistically, SPARCL1 acts directly on macrophages in vitro to induce the pro-inflammatory phenotype via activation of TLR4, and TLR4 inhibition in vivo ameliorates inflammatory exacerbations caused by endothelial Sparcl1 overexpression. Finally, we confirmed significant elevation of SPARCL1 in COVID-19 lung ECs in comparison with those from healthy donors. Survival analysis demonstrated that patients with fatal COVID-19 had higher levels of circulating SPARCL1 protein compared to those who recovered, indicating the potential of SPARCL1 as a biomarker for prognosis of pneumonia and suggesting that personalized medicine approaches might be harnessed to block SPARCL1 and improve outcomes in high-expressing patients.
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21
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Cheng X, Chen X, Zhang M, Wan Y, Ge S, Cheng X. Sparcl1 and Atherosclerosis. J Inflamm Res 2023; 16:2121-2127. [PMID: 37220502 PMCID: PMC10200116 DOI: 10.2147/jir.s406907] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 05/03/2023] [Indexed: 05/25/2023] Open
Abstract
Atherosclerosis and its complications constitute some of the major diseases affecting humans worldwide. A core component of atherogenesis is endothelial cell damage and dysfunction, which also includes factors such as adhesion and proliferation of various cells. Multiple studies have shown that atherosclerosis and cancer share a common pathophysiological process and exhibit a degree of similarity. Sparcl-1 is a cysteine-rich secretory stromal cell protein present in the extracellular matrix and belongs to the Sparc family of proteins. Its role in tumor development has been widely investigated; however, its role in cardiovascular diseases has rarely been studied. Sparcl-1 is considered an oncogene correlated with the regulation of cell adhesion, migration, and proliferation and is also related to blood vessel integrity. In this review, the potential link between Sparcl-1 and atherosclerosis development is investigated, and recommendations on future research on the role of Sparcl-1 in atherogenesis are provided.
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Affiliation(s)
- Xu Cheng
- Department of Cardiovascular Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, People’s Republic of China
- Laboratory of Molecular Biology and Department of Biochemistry, Anhui Medical University, Hefei, Anhui, 230022, People’s Republic of China
| | - Xinyan Chen
- Laboratory of Molecular Biology and Department of Biochemistry, Anhui Medical University, Hefei, Anhui, 230022, People’s Republic of China
- Department of Clinical Laboratory, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, People’s Republic of China
| | - Min Zhang
- Department of Clinical Laboratory, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, People’s Republic of China
| | - Yufeng Wan
- Department of Otolaryngology-Head Neck Surgery, the Affiliated Chaohu Hospital of Anhui Medical University, Hefei, Anhui, 238001, People’s Republic of China
| | - Shenglin Ge
- Department of Cardiovascular Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, People’s Republic of China
| | - Xiaowen Cheng
- Laboratory of Molecular Biology and Department of Biochemistry, Anhui Medical University, Hefei, Anhui, 230022, People’s Republic of China
- Department of Clinical Laboratory, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, People’s Republic of China
- Anhui Province Key Laboratory of Translational Cancer Research, Bengbu Medical College, Bengbu, Anhui, 233030, People’s Republic of China
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22
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Zanini F, Che X, Knutsen C, Liu M, Suresh NE, Domingo-Gonzalez R, Dou SH, Zhang D, Pryhuber GS, Jones RC, Quake SR, Cornfield DN, Alvira CM. Developmental diversity and unique sensitivity to injury of lung endothelial subtypes during postnatal growth. iScience 2023; 26:106097. [PMID: 36879800 PMCID: PMC9984561 DOI: 10.1016/j.isci.2023.106097] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 12/20/2022] [Accepted: 01/25/2023] [Indexed: 02/01/2023] Open
Abstract
At birth, the lung is still immature, heightening susceptibility to injury but enhancing regenerative capacity. Angiogenesis drives postnatal lung development. Therefore, we profiled the transcriptional ontogeny and sensitivity to injury of pulmonary endothelial cells (EC) during early postnatal life. Although subtype speciation was evident at birth, immature lung EC exhibited transcriptomes distinct from mature counterparts, which progressed dynamically over time. Gradual, temporal changes in aerocyte capillary EC (CAP2) contrasted with more marked alterations in general capillary EC (CAP1) phenotype, including distinct CAP1 present only in the early alveolar lung expressing Peg3, a paternally imprinted transcription factor. Hyperoxia, an injury that impairs angiogenesis induced both common and unique endothelial gene signatures, dysregulated capillary EC crosstalk, and suppressed CAP1 proliferation while stimulating venous EC proliferation. These data highlight the diversity, transcriptomic evolution, and pleiotropic responses to injury of immature lung EC, possessing broad implications for lung development and injury across the lifespan.
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Affiliation(s)
- Fabio Zanini
- Prince of Wales Clinical School, Lowy Cancer Research Centre, University of New South Wales, Sydney, Kensington, NSW 2052, Australia
| | - Xibing Che
- Center for Excellence in Pulmonary Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
- Division of Pulmonary, Asthma and Sleep Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Carsten Knutsen
- Center for Excellence in Pulmonary Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
- Division of Critical Care Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Min Liu
- Center for Excellence in Pulmonary Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
- Division of Critical Care Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Nina E. Suresh
- Center for Excellence in Pulmonary Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
- Division of Pulmonary, Asthma and Sleep Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Racquel Domingo-Gonzalez
- Center for Excellence in Pulmonary Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
- Division of Critical Care Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Steve H. Dou
- Center for Excellence in Pulmonary Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
- Division of Critical Care Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Daoqin Zhang
- Center for Excellence in Pulmonary Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
- Division of Critical Care Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Gloria S. Pryhuber
- Division of Neonatology, Department of Pediatrics, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Robert C. Jones
- Department of Bioengineering, Stanford University, Stanford, CA 94305, USA
| | - Stephen R. Quake
- Department of Bioengineering, Stanford University, Stanford, CA 94305, USA
- Chan Zuckerberg Biohub, San Francisco, CA 94158, USA
- Department of Applied Physics, Stanford University, Stanford, CA 94305, USA
| | - David N. Cornfield
- Center for Excellence in Pulmonary Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
- Division of Pulmonary, Asthma and Sleep Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Cristina M. Alvira
- Center for Excellence in Pulmonary Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
- Division of Critical Care Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
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23
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Fang Q, Stehr AM, Naschberger E, Knopf J, Herrmann M, Stürzl M. No NETs no TIME: Crosstalk between neutrophil extracellular traps and the tumor immune microenvironment. Front Immunol 2022; 13:1075260. [PMID: 36618417 PMCID: PMC9816414 DOI: 10.3389/fimmu.2022.1075260] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 12/05/2022] [Indexed: 12/24/2022] Open
Abstract
The tumor immune microenvironment (TIME) controls tumorigenesis. Neutrophils are important components of TIME and control tumor progression and therapy resistance. Neutrophil extracellular traps (NETs) ejected by activated neutrophils are net-like structures composed of decondensed extracellular chromatin filaments decorated with a plethora of granules as well as cytoplasmic proteins. Many of these harbour post translational modifications. Cancer cells reportedly trigger NET formation, and conversely, NETs alter the TIME and promote tumor cell proliferation and migration. The specific interactions between NETs and TIME and the respective effects on tumor progression are still elusive. In certain tumors, a CD4+ T helper (Th) 2 cell-associated TIME induces NETs and exerts immunosuppressive functions via programmed death 1 (PD-1)/PD-L1, both associated with poorer prognosis. In other cases, NETs induce the proliferation of Th1 cells, associated with an improved prognosis in cancer. In addition, NETs can drive macrophage polarization and often rely on macrophages to promote cancer cell invasion and metastasis. In turn, macrophages can swiftly clear NETs in an immunologically silent manner. The aim of this review is to summarize the knowledge about the mutual interaction between NETs and TIME and its impact on tumor growth and therapy.
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Affiliation(s)
- Qi Fang
- Division of Molecular and Experimental Surgery, Translational Research Center, Department of Surgery, Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Antonia Margarethe Stehr
- Division of Molecular and Experimental Surgery, Translational Research Center, Department of Surgery, Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Elisabeth Naschberger
- Division of Molecular and Experimental Surgery, Translational Research Center, Department of Surgery, Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
- Comprehensive Cancer Center Erlangen-Europäische Metropolregion Nürnberg (EMN), Universitätsklinikum Erlangen, Erlangen, Germany
| | - Jasmin Knopf
- Department of Internal Medicine 3, Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Martin Herrmann
- Department of Internal Medicine 3, Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Michael Stürzl
- Division of Molecular and Experimental Surgery, Translational Research Center, Department of Surgery, Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
- Comprehensive Cancer Center Erlangen-Europäische Metropolregion Nürnberg (EMN), Universitätsklinikum Erlangen, Erlangen, Germany
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24
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Iwayama T, Iwashita M, Miyashita K, Sakashita H, Matsumoto S, Tomita K, Bhongsatiern P, Kitayama T, Ikegami K, Shimbo T, Tamai K, Murayama MA, Ogawa S, Iwakura Y, Yamada S, Olson LE, Takedachi M, Murakami S. Plap-1 lineage tracing and single-cell transcriptomics reveal cellular dynamics in the periodontal ligament. Development 2022; 149:277273. [DOI: 10.1242/dev.201203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 09/05/2022] [Indexed: 01/25/2023]
Abstract
ABSTRACT
Periodontal tissue supports teeth in the alveolar bone socket via fibrous attachment of the periodontal ligament (PDL). The PDL contains periodontal fibroblasts and stem/progenitor cells, collectively known as PDL cells (PDLCs), on top of osteoblasts and cementoblasts on the surface of alveolar bone and cementum, respectively. However, the characteristics and lineage hierarchy of each cell type remain poorly defined. This study identified periodontal ligament associated protein-1 (Plap-1) as a PDL-specific extracellular matrix protein. We generated knock-in mice expressing CreERT2 and GFP specifically in Plap-1-positive PDLCs. Genetic lineage tracing confirmed the long-standing hypothesis that PDLCs differentiate into osteoblasts and cementoblasts. A PDL single-cell atlas defined cementoblasts and osteoblasts as Plap-1−Ibsp+Sparcl1+ and Plap-1−Ibsp+Col11a2+, respectively. Other populations, such as Nes+ mural cells, S100B+ Schwann cells, and other non-stromal cells, were also identified. RNA velocity analysis suggested that a Plap-1highLy6a+ cell population was the source of PDLCs. Lineage tracing of Plap-1+ PDLCs during periodontal injury showed periodontal tissue regeneration by PDLCs. Our study defines diverse cell populations in PDL and clarifies the role of PDLCs in periodontal tissue homeostasis and repair.
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Affiliation(s)
- Tomoaki Iwayama
- Osaka University Graduate School of Dentistry 1 Department of Periodontology , , Suita, Osaka 565-0871 , Japan
| | - Mizuho Iwashita
- Osaka University Graduate School of Dentistry 1 Department of Periodontology , , Suita, Osaka 565-0871 , Japan
| | | | - Hiromi Sakashita
- Osaka University Graduate School of Dentistry 1 Department of Periodontology , , Suita, Osaka 565-0871 , Japan
- StemRIM Institute of Regeneration-Inducing Medicine, Osaka University 3 , Suita 565-0871 , Japan
| | - Shuji Matsumoto
- Osaka University Graduate School of Dentistry 1 Department of Periodontology , , Suita, Osaka 565-0871 , Japan
| | - Kiwako Tomita
- Osaka University Graduate School of Dentistry 1 Department of Periodontology , , Suita, Osaka 565-0871 , Japan
| | - Phan Bhongsatiern
- Osaka University Graduate School of Dentistry 1 Department of Periodontology , , Suita, Osaka 565-0871 , Japan
| | - Tomomi Kitayama
- StemRIM Inc. 2 , Ibaraki, Osaka 567-0085 , Japan
- Osaka University Graduate School of Medicine 4 Department of Stem Cell Therapy Science , , Osaka 565-0871 , Japan
| | | | - Takashi Shimbo
- StemRIM Institute of Regeneration-Inducing Medicine, Osaka University 3 , Suita 565-0871 , Japan
- Osaka University Graduate School of Medicine 4 Department of Stem Cell Therapy Science , , Osaka 565-0871 , Japan
| | - Katsuto Tamai
- Osaka University Graduate School of Medicine 4 Department of Stem Cell Therapy Science , , Osaka 565-0871 , Japan
| | - Masanori A. Murayama
- Research Institute for Biomedical Sciences, Tokyo University of Science 5 , Noda, Chiba 278-8510 , Japan
| | - Shuhei Ogawa
- Research Institute for Biomedical Sciences, Tokyo University of Science 5 , Noda, Chiba 278-8510 , Japan
| | - Yoichiro Iwakura
- Research Institute for Biomedical Sciences, Tokyo University of Science 5 , Noda, Chiba 278-8510 , Japan
| | - Satoru Yamada
- Tohoku University Graduate School of Dentistry 6 Department of Periodontology and Endodontology , , Sendai, Miyagi 980-8575 , Japan
| | - Lorin E. Olson
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation 7 , Oklahoma City, OK 73104 , USA
| | - Masahide Takedachi
- Osaka University Graduate School of Dentistry 1 Department of Periodontology , , Suita, Osaka 565-0871 , Japan
| | - Shinya Murakami
- Osaka University Graduate School of Dentistry 1 Department of Periodontology , , Suita, Osaka 565-0871 , Japan
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25
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Voigt AP, Mullin NK, Mulfaul K, Lozano LP, Wiley LA, Flamme-Wiese MJ, Boese EA, Han IC, Scheetz TE, Stone EM, Tucker BA, Mullins RF. Choroidal endothelial and macrophage gene expression in atrophic and neovascular macular degeneration. Hum Mol Genet 2022; 31:2406-2423. [PMID: 35181781 PMCID: PMC9307320 DOI: 10.1093/hmg/ddac043] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Revised: 01/22/2022] [Accepted: 02/06/2022] [Indexed: 11/22/2022] Open
Abstract
The human choroid is a heterogeneous, highly vascular connective tissue that dysfunctions in age-related macular degeneration (AMD). In this study, we performed single-cell RNA sequencing on 21 human choroids, 11 of which were derived from donors with early atrophic or neovascular AMD. Using this large donor cohort, we identified new gene expression signatures and immunohistochemically characterized discrete populations of resident macrophages, monocytes/inflammatory macrophages and dendritic cells. These three immune populations demonstrated unique expression patterns for AMD genetic risk factors, with dendritic cells possessing the highest expression of the neovascular AMD-associated MMP9 gene. Additionally, we performed trajectory analysis to model transcriptomic changes across the choroidal vasculature, and we identified expression signatures for endothelial cells from choroidal arterioles and venules. Finally, we performed differential expression analysis between control, early atrophic AMD, and neovascular AMD samples, and we observed that early atrophic AMD samples had high expression of SPARCL1, a gene that has been shown to increase in response to endothelial damage. Likewise, neovascular endothelial cells harbored gene expression changes consistent with endothelial cell damage and demonstrated increased expression of the sialomucins CD34 and ENCM, which were also observed at the protein level within neovascular membranes. Overall, this study characterizes the molecular features of new populations of choroidal endothelial cells and mononuclear phagocytes in a large cohort of AMD and control human donors.
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Affiliation(s)
- Andrew P Voigt
- Department of Ophthalmology and Visual Sciences, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
- Institute for Vision Research, The University of Iowa, Iowa City, IA 52242, USA
| | - Nathaniel K Mullin
- Department of Ophthalmology and Visual Sciences, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
- Institute for Vision Research, The University of Iowa, Iowa City, IA 52242, USA
| | - Kelly Mulfaul
- Department of Ophthalmology and Visual Sciences, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
- Institute for Vision Research, The University of Iowa, Iowa City, IA 52242, USA
| | - Lola P Lozano
- Department of Ophthalmology and Visual Sciences, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
- Institute for Vision Research, The University of Iowa, Iowa City, IA 52242, USA
| | - Luke A Wiley
- Department of Ophthalmology and Visual Sciences, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
- Institute for Vision Research, The University of Iowa, Iowa City, IA 52242, USA
| | - Miles J Flamme-Wiese
- Department of Ophthalmology and Visual Sciences, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
- Institute for Vision Research, The University of Iowa, Iowa City, IA 52242, USA
| | - Erin A Boese
- Department of Ophthalmology and Visual Sciences, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
- Institute for Vision Research, The University of Iowa, Iowa City, IA 52242, USA
| | - Ian C Han
- Department of Ophthalmology and Visual Sciences, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
- Institute for Vision Research, The University of Iowa, Iowa City, IA 52242, USA
| | - Todd E Scheetz
- Department of Ophthalmology and Visual Sciences, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
- Institute for Vision Research, The University of Iowa, Iowa City, IA 52242, USA
| | - Edwin M Stone
- Department of Ophthalmology and Visual Sciences, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
- Institute for Vision Research, The University of Iowa, Iowa City, IA 52242, USA
| | - Budd A Tucker
- Department of Ophthalmology and Visual Sciences, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
- Institute for Vision Research, The University of Iowa, Iowa City, IA 52242, USA
| | - Robert F Mullins
- Department of Ophthalmology and Visual Sciences, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
- Institute for Vision Research, The University of Iowa, Iowa City, IA 52242, USA
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26
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Shen C, Han L, Liu B, Zhang G, Cai Z, Yin X, Yin Y, Chen Z, Zhang B. The KDM6A-SPARCL1 axis blocks metastasis and regulates the tumour microenvironment of gastrointestinal stromal tumours by inhibiting the nuclear translocation of p65. Br J Cancer 2022; 126:1457-1469. [PMID: 35136209 PMCID: PMC9090789 DOI: 10.1038/s41416-022-01728-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 01/07/2022] [Accepted: 01/28/2022] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND It is urgent to explore the pathogenic mechanism of gastrointestinal stromal tumours (GISTs). KDM6A, a histone demethylase, can activate gene transcription and has not been reported in GISTs. SPARCL1 may serve as a metastasis marker in GIST, but the molecular mechanism remains to be further explored. This study aimed to explore the biological function and molecular mechanism of KDM6A and SPARCL1 in GIST. METHODS CCK-8, live cell count, colony formation, wound-healing and Transwell migration and invasion assays were employed to detect the cell proliferation, migration and invasion. A xenograft model and hepatic metastasis model were used to assess the role of KDM6A and SPARCL1 in vivo. RESULTS KDM6A inhibited the proliferation, migration and invasion of GIST cells. Mechanistically, KDM6A promotes the transcription of SPARCL1 by demethylating histone H3 lysine trimethylation and consequently leads to the inactivation of p65. SPARCL1 affected the metastasis of GIST cells in a mesenchymal-epithelial transition- and matrix-metalloproteinase-dependent manner. SPARCL1 knockdown promoted angiogenesis, M2 polarisation and macrophage recruitment by inhibiting the phosphorylation of p65. Moreover, KDM6A and SPARCL1 inhibited hepatic metastasis and macrophage infiltration in vivo. CONCLUSIONS Our findings establish the critical role of the KDM6A-SPARCL1-p65 axis in restraining the malignancy of GIST.
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Affiliation(s)
- Chaoyong Shen
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
| | - Luyin Han
- Intensive care unit, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
| | - Baike Liu
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
| | - Guixiang Zhang
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
| | - Zhaolun Cai
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
| | - Xiaonan Yin
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
| | - Yuan Yin
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
| | - Zhixin Chen
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
| | - Bo Zhang
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China.
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27
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Yan H, Shi J, Dai Y, Li X, Wu Y, Zhang J, Gu Z, Zhang C, Leng J. Technique integration of single-cell RNA sequencing with spatially resolved transcriptomics in the tumor microenvironment. Cancer Cell Int 2022; 22:155. [PMID: 35440049 PMCID: PMC9020011 DOI: 10.1186/s12935-022-02580-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Accepted: 04/08/2022] [Indexed: 12/05/2022] Open
Abstract
Background The tumor microenvironment contributes to tumor initiation, growth, invasion, and metastasis. The tumor microenvironment is heterogeneous in cellular and acellular components, particularly structural features and their gene expression at the inter-and intra-tumor levels. Main text Single-cell RNA sequencing profiles single-cell transcriptomes to reveal cell proportions and trajectories while spatial information is lacking. Spatially resolved transcriptomics redeems this lack with limited coverage or depth of transcripts. Hence, the integration of single-cell RNA sequencing and spatial data makes the best use of their strengths, having insights into exploring diverse tissue architectures and interactions in a complicated network. We review applications of integrating the two methods, especially in cellular components in the tumor microenvironment, showing each role in cancer initiation and progression, which provides clinical relevance in prognosis, optimal treatment, and potential therapeutic targets. Conclusion The integration of two approaches may break the bottlenecks in the spatial resolution of neighboring cell subpopulations in cancer, and help to describe the signaling circuitry about the intercommunication and its exact mechanisms in producing different types and malignant stages of tumors.
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Affiliation(s)
- Hailan Yan
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan Dongcheng District, Beijing, 100730, China.,National Clinical Research Center for Obstetric & Gynecologic Diseases, No.1 Shuaifuyuan Dongcheng District, Beijing, 100730, China
| | - Jinghua Shi
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan Dongcheng District, Beijing, 100730, China.,National Clinical Research Center for Obstetric & Gynecologic Diseases, No.1 Shuaifuyuan Dongcheng District, Beijing, 100730, China
| | - Yi Dai
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan Dongcheng District, Beijing, 100730, China.,National Clinical Research Center for Obstetric & Gynecologic Diseases, No.1 Shuaifuyuan Dongcheng District, Beijing, 100730, China
| | - Xiaoyan Li
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan Dongcheng District, Beijing, 100730, China.,National Clinical Research Center for Obstetric & Gynecologic Diseases, No.1 Shuaifuyuan Dongcheng District, Beijing, 100730, China
| | - Yushi Wu
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan Dongcheng District, Beijing, 100730, China.,National Clinical Research Center for Obstetric & Gynecologic Diseases, No.1 Shuaifuyuan Dongcheng District, Beijing, 100730, China
| | - Jing Zhang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan Dongcheng District, Beijing, 100730, China.,National Clinical Research Center for Obstetric & Gynecologic Diseases, No.1 Shuaifuyuan Dongcheng District, Beijing, 100730, China
| | - Zhiyue Gu
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan Dongcheng District, Beijing, 100730, China.,National Clinical Research Center for Obstetric & Gynecologic Diseases, No.1 Shuaifuyuan Dongcheng District, Beijing, 100730, China
| | - Chenyu Zhang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan Dongcheng District, Beijing, 100730, China.,National Clinical Research Center for Obstetric & Gynecologic Diseases, No.1 Shuaifuyuan Dongcheng District, Beijing, 100730, China
| | - Jinhua Leng
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan Dongcheng District, Beijing, 100730, China. .,National Clinical Research Center for Obstetric & Gynecologic Diseases, No.1 Shuaifuyuan Dongcheng District, Beijing, 100730, China.
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28
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Zhang S, Li Y, Li Z, Wang G, Liao A, Wang J, Li H, Guo Z, Cheng B, Zhang X. Intelligent Nanodelivery System-Generated 1 O 2 Mediates Tumor Vessel Normalization by Activating Endothelial TRPV4-eNOS Signaling. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2022; 18:e2200038. [PMID: 35332670 DOI: 10.1002/smll.202200038] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 02/20/2022] [Indexed: 06/14/2023]
Abstract
Tumor microenvironment (TME)-responsive intelligent photodynamic therapy (PDT) systems have attracted increasing interest in anticancer therapy, due to their potential to address significant and unsatisfactory therapeutic issues, such as limited tissue penetration, inevitable normal tissue damage, and excessive impaired vessels. Here, an H2 O2 -triggered intelligent LCL/ZnO PDT nanodelivery system is elaborately designed. LCL/ZnO can selectively regulate tumor-derived endothelial cells (TECs) and specifically kill tumor cells, by responding to different H2 O2 gradients in TECs and tumor cells. The LCL/ZnO is able to normalize tumor vessels, thereby resulting in decreased metastases, and ameliorating the immunosuppressive TME. Further analysis demonstrates that singlet oxygen (1 O2 )-activated transient receptor potential vanilloid-4-endothelial nitric oxide synthase signals generated in TECs by LCL/ZnO induce tumor vascular normalization, which is identified as a novel mechanism contributing to the increased ability of PDT to promote cancer therapy. In conclusion, designing an intelligent PDT nanodelivery system response to the TME, that includes both selective TECs regulation and specific tumor-killing, will facilitate the development of effective interventions for future clinical applications.
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Affiliation(s)
- Shuaiqiang Zhang
- Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Yuanhao Li
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
- Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Zhuoyue Li
- Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Guangxue Wang
- Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Ai Liao
- Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Jingru Wang
- Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Hui Li
- Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Zefeng Guo
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
- Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Boyang Cheng
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
- Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
| | - Xuan Zhang
- Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
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29
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Li J, Chen D, Shen M. Tumor Microenvironment Shapes Colorectal Cancer Progression, Metastasis, and Treatment Responses. Front Med (Lausanne) 2022; 9:869010. [PMID: 35402443 PMCID: PMC8984105 DOI: 10.3389/fmed.2022.869010] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 02/24/2022] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most devastating diseases that accounts for numerous deaths worldwide. Tumor cell-autonomous pathways, such as the oncogenic signaling activation, significantly contribute to CRC progression and metastasis. Recent accumulating evidence suggests that the CRC microenvironment also profoundly promotes or represses this process. As the roles of the tumor microenvironment (TME) in CRC progression and metastasis is gradually uncovered, the importance of these non-cell-autonomous signaling pathways is appreciated. However, we are still at the beginning of this TME function exploring process. In this review, we summarize the current understanding of the TME in CRC progression and metastasis by focusing on the gut microbiota and host cellular and non-cellular components. We also briefly discuss TME-remodeling therapies in CRC.
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Affiliation(s)
- Jun Li
- Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, United States
| | - Dawei Chen
- Wayne State University School of Medicine, Detroit, MI, United States
| | - Minhong Shen
- Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, United States
- Department of Oncology, Wayne State University School of Medicine and Tumor Biology and Microenvironment Research Program, Barbara Ann Karmanos Cancer Institute, Detroit, MI, United States
- *Correspondence: Minhong Shen,
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30
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SPARCL1 Is a Novel Prognostic Biomarker and Correlates with Tumor Microenvironment in Colorectal Cancer. BIOMED RESEARCH INTERNATIONAL 2022; 2022:1398268. [PMID: 35111844 PMCID: PMC8803425 DOI: 10.1155/2022/1398268] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Revised: 10/05/2021] [Accepted: 12/23/2021] [Indexed: 12/24/2022]
Abstract
Background Secreted protein acidic and rich in cysteine-like 1 (SPARCL1) plays an important role in tumor pathogenesis. We aim to evaluate the clinical significance and potential biological roles of SPARCL1 in colorectal cancer (CRC). Methods Datasets from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were downloaded to evaluate the expression levels of SPARCL1 in CRC. Receiver operating characteristic (ROC) curve was constructed to evaluate the diagnostic value of SPARCL1. Then, comprehensive database search was conducted for published clinical studies to explore clinical significance of SPARCL1. In addition, coexpression genes of SPARCL1 were identified through the cBioPortal database and enrichment analysis of SPARCL1 and its coexpression genes were performed by the “clusterProfiler” R package. Finally, the correlations between SPARCL1 and tumor microenvironment scores, tumor-infiltrating immune cells in CRC were determined by “ESTIMATE” and “GSVA” R packages. Results SPARCL1 was significantly downregulated in CRC tissues, and SPARCL1 showed high accuracy for diagnosis of primary CRC in both GEO and TCGA datasets. Pooled results from published clinical studies showed SPARCL1 expression was associated with differentiation (OR = 1.89, 95% CI: 1.38-2.59), tumor stage (OR = 0.47, 95% CI: 0.29-0.77), distant metastasis (OR = 0.53, 95% CI: 0.33-0.84), and overall survival (HR = 0.56, 95% CI: 0.43-0.74). SPARCL1 and its top 300 coexpression genes were involved in several KEGG pathways, such as focal adhesion, cell adhesion molecules, PI3K-Akt signaling pathway, cGMP-PKG signaling pathway, and ECM-receptor interaction. Besides, the SPARCL1 expression was significantly correlated with stromal score, immune score, ESTIMATE score, and diverse immune cells. Conclusion SPARCL1 significantly correlated with clinicopathological features and tumor microenvironment in CRC.
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Chen WJ, Cao H, Cao JW, Zuo L, Qu FJ, Xu D, Zhang H, Gong HY, Chen JX, Ye JQ, Gan SS, Zhou W, Zhu DW, Pan XW, Cui XG. Heterogeneity of tumor microenvironment is associated with clinical prognosis of non-clear cell renal cell carcinoma: a single-cell genomics study. Cell Death Dis 2022; 13:50. [PMID: 35017463 PMCID: PMC8752784 DOI: 10.1038/s41419-022-04501-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 12/08/2021] [Accepted: 01/04/2022] [Indexed: 12/18/2022]
Abstract
Non-clear renal cell carcinomas (nccRCCs) are less frequent in kidney cancer with histopathological heterogeneity. A better understanding of the tumor biology of nccRCC can provide more effective treatment paradigms for different subtypes. To reveal the heterogeneity of tumor microenvironment (TME) in nccRCC, we performed 10x sing-cell genomics on tumor and normal tissues from patients with papillary renal cell carcinoma (pRCC), chromophobe RCC (chrRCC), collecting duct carcinoma (CDRCC) and sarcomatoid RCC (sarRCC). 15 tissue samples were finally included. 34561 cells were identified as 16 major cell clusters with 34 cell subtypes. Our study presented the sing-cell landscape for four types of nccRCC, and demonstrated that CD8+ T cells exhaustion, tumor-associated macrophages (TAMs) and sarcomatoid process were the pivotal factors in immunosuppression of nccRCC tissues and were closely correlated with poor prognosis. Abnormal metabolic patterns were present in both cancer cells and tumor-infiltrating stromal cells, such as fibroblasts and endothelial cells. Combined with CIBERSORTx tool, the expression data of bulk RNA-seq from TCGA were labeled with cell types of our sing-cell data. Calculation of the relative abundance of cell types revealed that greater proportion of exhausted CD8+ T cells, TAMs and sarRCC derived cells were correlated with poor prognosis in the cohort of 274 nccRCC patients. To the best of our knowledge, this is the first study that provides a more comprehensive sight about the heterogeneity and tumor biology of nccRCC, which may potentially facilitate the development of more effective therapies for nccRCC.
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Affiliation(s)
- Wen-Jin Chen
- Department of Urology, The Third Affiliated Hospital of Second Military Medical University, 700 North Moyu Road, Shanghai, 201805, China
| | - Hao Cao
- School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, 110016, China.,Peking-Tsinghua Center for Life Sciences, Tsinghua University, 100084, Beijing, China
| | - Jian-Wei Cao
- Department of Urology, Xinhua Hospital, Shanghai Jiaotong University, School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Li Zuo
- Department of Urology, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, 29 Xinglong Road, Changzhou, 213000, Jiangsu, China
| | - Fa-Jun Qu
- Department of Urology, Xinhua Hospital, Shanghai Jiaotong University, School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Da Xu
- Department of Urology, The Third Affiliated Hospital of Second Military Medical University, 700 North Moyu Road, Shanghai, 201805, China
| | - Hao Zhang
- Department of Orthopedic Oncology, Changzheng Hospital of Second Military Medical University, 415 Fengyang Road, Shanghai, 200003, China
| | - Hai-Yi Gong
- Department of Orthopedic Oncology, Changzheng Hospital of Second Military Medical University, 415 Fengyang Road, Shanghai, 200003, China
| | - Jia-Xin Chen
- Department of Urology, The Third Affiliated Hospital of Second Military Medical University, 700 North Moyu Road, Shanghai, 201805, China
| | - Jian-Qing Ye
- Department of Urology, The Third Affiliated Hospital of Second Military Medical University, 700 North Moyu Road, Shanghai, 201805, China
| | - Si-Shun Gan
- Department of Urology, The Third Affiliated Hospital of Second Military Medical University, 700 North Moyu Road, Shanghai, 201805, China
| | - Wang Zhou
- Department of Urology, The Third Affiliated Hospital of Second Military Medical University, 700 North Moyu Road, Shanghai, 201805, China.,Department of Urology, Xinhua Hospital, Shanghai Jiaotong University, School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Da-Wei Zhu
- Department of Urology, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, 29 Xinglong Road, Changzhou, 213000, Jiangsu, China.
| | - Xiu-Wu Pan
- Department of Urology, The Third Affiliated Hospital of Second Military Medical University, 700 North Moyu Road, Shanghai, 201805, China. .,Department of Urology, Xinhua Hospital, Shanghai Jiaotong University, School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China.
| | - Xin-Gang Cui
- Department of Urology, The Third Affiliated Hospital of Second Military Medical University, 700 North Moyu Road, Shanghai, 201805, China. .,Department of Urology, Xinhua Hospital, Shanghai Jiaotong University, School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China.
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Hu C, Wang S, Lin L, Qi H, Lin H, Jia X, Zhu Y, Wu X, Li M, Wang T, Zhao Z, Xu M, Xu Y, Wang W, Ning G, Bi Y, Li D, Chen Y, Dai M, Lu J. Association of serum secreted protein acidic and rich in cysteine-like protein 1 with metabolic measures and dyslipidemia among Chinese adults. Front Endocrinol (Lausanne) 2022; 13:1018657. [PMID: 36387870 PMCID: PMC9647160 DOI: 10.3389/fendo.2022.1018657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Accepted: 10/12/2022] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVES Recent studies found that secreted protein acidic and rich in cysteine-like protein 1 (Sparcl1) could inhibit lipid droplets accumulation by peroxisome proliferator-activated receptor-gamma (PPARγ) signal pathway. However, the associations of serum Sparcl1 level with lipids profiles and other metabolic phenotypes remain unknown in human population study. METHODS We determined serum Sparcl1 using sandwich enzyme-linked immunosorbent assays among 1750 adults aged 40 years and older from a community in Shanghai, China. Generalized linear regression models were used to evaluate the association between Sparcl1 and metabolic measures. Multivariable-adjusted logistic regression analyses were performed to evaluate the relationship of serum Sparcl1 with prevalent dyslipidemia. RESULTS With the increment of serum Sparcl1, participants tended to have lower level of triglycerides, and higher level of high-density lipoprotein cholesterol (all P for trend < 0.01). No significant associations between serum Sparcl1 and glucose, blood pressure, or body size were observed. The generalized linear regression models suggested that per standard deviation (SD) increment of serum Sparcl1 was significantly inversely associated with triglycerides (β= -0.06, P=0.02). The prevalence of dyslipidemia decreased across the sparcl1 quartiles (P for trend <0.01). After controlling the potential confounders, participants in the highest quartile of sparcl1 concentration had the lowest prevalence of dyslipidemia (odds ratio [OR], 0.69; 95% confidence interval [CI], 0.52-0.91), compared with the lowest quartile. Per SD increment of Sparcl1 was associated with 20% (OR, 0.80; 95%CI, 0.69-0.94) lower prevalence of hypertriglyceridemia and 12% (OR, 0.88; 95%CI, 0.79-0.97) lower prevalence of dyslipidemia. The association between serum Sparcl1 and dyslipidemia were generally consistent across subgroups (all P for interaction > 0.05). CONCLUSION Serum Sparcl1 was significantly associated with decreased risk of prevalent dyslipidemia in Chinese population. Further studies are warranted to confirm this association.
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Affiliation(s)
- Chunyan Hu
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shuangyuan Wang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lin Lin
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hongyan Qi
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hong Lin
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaojing Jia
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuanyue Zhu
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xueyan Wu
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Mian Li
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Tiange Wang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhiyun Zhao
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Min Xu
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yu Xu
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weiqing Wang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guang Ning
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yufang Bi
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Donghui Li
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Yuhong Chen
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Meng Dai
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Jieli Lu, ; Meng Dai,
| | - Jieli Lu
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Jieli Lu, ; Meng Dai,
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Stehr AM, Wang G, Demmler R, Stemmler MP, Straube J, Tripal P, Schmid B, Geppert CI, Hartmann A, Muñoz LE, Schoen J, Völkl S, Merkel S, Becker C, Schett G, Grützmann R, Naschberger E, Herrmann M, Stürzl M. Neutrophil extracellular traps drive epithelial‐mesenchymal transition of human colon cancer. J Pathol 2021; 256:455-467. [DOI: 10.1002/path.5860] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 12/13/2021] [Accepted: 12/20/2021] [Indexed: 11/08/2022]
Affiliation(s)
- Antonia M. Stehr
- Division of Molecular and Experimental Surgery, Translational Research Center, Department of Surgery Friedrich‐Alexander University (FAU) Erlangen‐Nürnberg and Universitätsklinikum Erlangen Erlangen Germany
| | - Guangxia Wang
- Division of Molecular and Experimental Surgery, Translational Research Center, Department of Surgery Friedrich‐Alexander University (FAU) Erlangen‐Nürnberg and Universitätsklinikum Erlangen Erlangen Germany
| | - Richard Demmler
- Division of Molecular and Experimental Surgery, Translational Research Center, Department of Surgery Friedrich‐Alexander University (FAU) Erlangen‐Nürnberg and Universitätsklinikum Erlangen Erlangen Germany
| | - Marc P. Stemmler
- Department of Experimental Medicine 1 Nikolaus‐Fiebiger Center for Molecular Medicine, Friedrich‐Alexander University (FAU) Erlangen‐Nürnberg Erlangen Germany
| | - Julia Straube
- Division of Molecular and Experimental Surgery, Translational Research Center, Department of Surgery Friedrich‐Alexander University (FAU) Erlangen‐Nürnberg and Universitätsklinikum Erlangen Erlangen Germany
| | - Philipp Tripal
- Optical Imaging Centre, Friedrich‐Alexander University Erlangen‐Nürnberg (FAU) Erlangen Germany
| | - Benjamin Schmid
- Optical Imaging Centre, Friedrich‐Alexander University Erlangen‐Nürnberg (FAU) Erlangen Germany
| | - Carol I. Geppert
- Institute of Pathology, Friedrich‐Alexander University (FAU) Erlangen‐Nürnberg and Universitätsklinikum Erlangen Erlangen Germany
| | - Arndt Hartmann
- Institute of Pathology, Friedrich‐Alexander University (FAU) Erlangen‐Nürnberg and Universitätsklinikum Erlangen Erlangen Germany
| | - Luis E. Muñoz
- Department of Internal Medicine 3 Friedrich‐Alexander University (FAU) Erlangen‐Nürnberg and Universitätsklinikum Erlangen Erlangen Germany
- Deutsches Zentrum für Immuntherapie (DZI), Friedrich‐Alexander University (FAU) Erlangen‐Nürnberg and Universitätsklinikum Erlangen Erlangen Germany
| | - Janina Schoen
- Department of Internal Medicine 3 Friedrich‐Alexander University (FAU) Erlangen‐Nürnberg and Universitätsklinikum Erlangen Erlangen Germany
- Deutsches Zentrum für Immuntherapie (DZI), Friedrich‐Alexander University (FAU) Erlangen‐Nürnberg and Universitätsklinikum Erlangen Erlangen Germany
| | - Simon Völkl
- Department of Internal Medicine 5 Friedrich‐Alexander University (FAU) Erlangen‐Nürnberg and Universitätsklinikum Erlangen Erlangen Germany
| | - Susanne Merkel
- Department of Surgery Friedrich‐Alexander University (FAU) Erlangen‐Nürnberg and Universitätsklinikum Erlangen Erlangen Germany
| | - Christoph Becker
- Department of Internal Medicine 1 Friedrich‐Alexander University (FAU) Erlangen‐Nürnberg and Universitätsklinikum Erlangen Erlangen Germany
| | - Georg Schett
- Department of Internal Medicine 3 Friedrich‐Alexander University (FAU) Erlangen‐Nürnberg and Universitätsklinikum Erlangen Erlangen Germany
- Deutsches Zentrum für Immuntherapie (DZI), Friedrich‐Alexander University (FAU) Erlangen‐Nürnberg and Universitätsklinikum Erlangen Erlangen Germany
| | - Robert Grützmann
- Department of Surgery Friedrich‐Alexander University (FAU) Erlangen‐Nürnberg and Universitätsklinikum Erlangen Erlangen Germany
| | - Elisabeth Naschberger
- Division of Molecular and Experimental Surgery, Translational Research Center, Department of Surgery Friedrich‐Alexander University (FAU) Erlangen‐Nürnberg and Universitätsklinikum Erlangen Erlangen Germany
| | - Martin Herrmann
- Department of Internal Medicine 3 Friedrich‐Alexander University (FAU) Erlangen‐Nürnberg and Universitätsklinikum Erlangen Erlangen Germany
- Deutsches Zentrum für Immuntherapie (DZI), Friedrich‐Alexander University (FAU) Erlangen‐Nürnberg and Universitätsklinikum Erlangen Erlangen Germany
| | - Michael Stürzl
- Division of Molecular and Experimental Surgery, Translational Research Center, Department of Surgery Friedrich‐Alexander University (FAU) Erlangen‐Nürnberg and Universitätsklinikum Erlangen Erlangen Germany
- Comprehensive Cancer Center Erlangen‐EMN Universitätsklinikum Erlangen Erlangen Germany
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Matrix Metalloproteinases Shape the Tumor Microenvironment in Cancer Progression. Int J Mol Sci 2021; 23:ijms23010146. [PMID: 35008569 PMCID: PMC8745566 DOI: 10.3390/ijms23010146] [Citation(s) in RCA: 223] [Impact Index Per Article: 55.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 12/20/2021] [Accepted: 12/21/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer progression with uncontrolled tumor growth, local invasion, and metastasis depends largely on the proteolytic activity of numerous matrix metalloproteinases (MMPs), which affect tissue integrity, immune cell recruitment, and tissue turnover by degrading extracellular matrix (ECM) components and by releasing matrikines, cell surface-bound cytokines, growth factors, or their receptors. Among the MMPs, MMP-14 is the driving force behind extracellular matrix and tissue destruction during cancer invasion and metastasis. MMP-14 also influences both intercellular as well as cell-matrix communication by regulating the activity of many plasma membrane-anchored and extracellular proteins. Cancer cells and other cells of the tumor stroma, embedded in a common extracellular matrix, interact with their matrix by means of various adhesive structures, of which particularly invadopodia are capable to remodel the matrix through spatially and temporally finely tuned proteolysis. As a deeper understanding of the underlying functional mechanisms is beneficial for the development of new prognostic and predictive markers and for targeted therapies, this review examined the current knowledge of the interplay of the various MMPs in the cancer context on the protein, subcellular, and cellular level with a focus on MMP14.
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Katkeviciute E, Hering L, Montalban-Arques A, Busenhart P, Schwarzfischer M, Manzini R, Conde J, Atrott K, Lang S, Rogler G, Naschberger E, Schellerer VS, Stürzl M, Rickenbacher A, Turina M, Weber A, Leibl S, Leventhal GE, Levesque M, Boyman O, Scharl M, Spalinger MR. Protein tyrosine phosphatase nonreceptor type 2 controls colorectal cancer development. J Clin Invest 2021; 131:140281. [PMID: 33001862 DOI: 10.1172/jci140281] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 09/29/2020] [Indexed: 12/31/2022] Open
Abstract
Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) recently emerged as a promising cancer immunotherapy target. We set out to investigate the functional role of PTPN2 in the pathogenesis of human colorectal carcinoma (CRC), as its role in immune-silent solid tumors is poorly understood. We demonstrate that in human CRC, increased PTPN2 expression and activity correlated with disease progression and decreased immune responses in tumor tissues. In particular, stage II and III tumors displayed enhanced PTPN2 protein expression in tumor-infiltrating T cells, and increased PTPN2 levels negatively correlated with expression of PD-1, CTLA4, STAT1, and granzyme A. In vivo, T cell- and DC-specific PTPN2 deletion reduced tumor burden in several CRC models by promoting CD44+ effector/memory T cells, as well as CD8+ T cell infiltration and cytotoxicity in the tumor. In direct relevance to CRC treatment, T cell-specific PTPN2 deletion potentiated anti-PD-1 efficacy and induced antitumor memory formation upon tumor rechallenge in vivo. Our data suggest a role for PTPN2 in suppressing antitumor immunity and promoting tumor development in patients with CRC. Our in vivo results identify PTPN2 as a key player in controlling the immunogenicity of CRC, with the strong potential to be exploited for cancer immunotherapy.
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Affiliation(s)
- Egle Katkeviciute
- Department of Gastroenterology and Hepatology, University Hospital Zurich, and
| | - Larissa Hering
- Department of Gastroenterology and Hepatology, University Hospital Zurich, and
| | | | - Philipp Busenhart
- Department of Gastroenterology and Hepatology, University Hospital Zurich, and
| | | | - Roberto Manzini
- Department of Gastroenterology and Hepatology, University Hospital Zurich, and
| | - Javier Conde
- Department of Gastroenterology and Hepatology, University Hospital Zurich, and
| | - Kirstin Atrott
- Department of Gastroenterology and Hepatology, University Hospital Zurich, and
| | - Silvia Lang
- Department of Gastroenterology and Hepatology, University Hospital Zurich, and
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital Zurich, and.,Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | | | - Vera S Schellerer
- Department of Surgery, University Medical Center of Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | | | | | | | - Achim Weber
- Department of Pathology, University Hospital Zurich, Zurich, Switzerland
| | - Sebastian Leibl
- Department of Pathology, University Hospital Zurich, Zurich, Switzerland
| | - Gabriel E Leventhal
- Department of Civil and Environmental Engineering, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA
| | | | - Onur Boyman
- Department of Immunology, University Hospital Zurich, Zurich, Switzerland.,Faculty of Medicine, University of Zurich, Zurich, Switzerland
| | - Michael Scharl
- Department of Gastroenterology and Hepatology, University Hospital Zurich, and.,Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
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Hu H, Wu D, Liu X, Yu H, Xu J, Cai W, Huang Y, Bai R, Zhang J, Gu Y, Zheng S, Ge W. SPARCL1 exhibits different expressions in left- and right-sided colon cancer and is downregulated via DNA methylation. Epigenomics 2021; 13:1269-1282. [PMID: 34435512 DOI: 10.2217/epi-2021-0231] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Aim: The authors previously found that SPARCL1 functions to suppress colorectal cancer metastasis. Here, the epigenetic mechanism of SPARCL1 regulation and its relationship with clinicopathological features in colon cancer were investigated. Materials & methods: SPARCL1 expression was evaluated by immunohistochemistry staining in a tissue array containing 271 left-sided colon cancer samples and 257 right-sided colon cancer samples. In vivo and in vitro DNA methylation states were measured by biochemical sulfide potential assay. The transcription and DNA methylation states in cells were altered by siRNA or decitabine treatment, respectively. Cellular motility properties were compared through transwell assay. Results & conclusion: SPARCL1, mediated by its DNA methylation, may arrest colorectal carcinoma motility. Furthermore, SPARCL1 expression is higher and may have a specific prognostic value in left-sided colon cancer.
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Affiliation(s)
- Hanguang Hu
- Cancer Institute, Key Laboratory of Cancer Prevention & Intervention, China National Ministry of Education; Key Laboratory of Molecular Biology in Medical Sciences; the Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou 310009, Zhejiang Province, China.,Department of Oncology, the Second Affiliated Hospital of Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou, 310009, Zhejiang Province, China
| | - Dehao Wu
- Cancer Institute, Key Laboratory of Cancer Prevention & Intervention, China National Ministry of Education; Key Laboratory of Molecular Biology in Medical Sciences; the Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou 310009, Zhejiang Province, China
| | - Xibo Liu
- Department of Pathology, Shaoxing People's Hospital, No. 568, Zhongxing North Road, Shaoxing, 312000, Zhejiang Province, China
| | - Haifeng Yu
- Department of Oncology, the Second Affiliated Hospital of Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou, 310009, Zhejiang Province, China.,Department of Lymphatic Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, 310005, Zhejiang Province, China.,Institute of Cancer & Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang Province, China
| | - Junxi Xu
- Department of Gastroenterology, the Second Affiliated Hospital of Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou, 310009, Zhejiang Province, China
| | - Wen Cai
- Cancer Institute, Key Laboratory of Cancer Prevention & Intervention, China National Ministry of Education; Key Laboratory of Molecular Biology in Medical Sciences; the Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou 310009, Zhejiang Province, China.,Department of Gastroenterology, the Second Affiliated Hospital of Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou, 310009, Zhejiang Province, China
| | - Yanqin Huang
- Cancer Institute, Key Laboratory of Cancer Prevention & Intervention, China National Ministry of Education; Key Laboratory of Molecular Biology in Medical Sciences; the Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou 310009, Zhejiang Province, China
| | - Rui Bai
- Cancer Institute, Key Laboratory of Cancer Prevention & Intervention, China National Ministry of Education; Key Laboratory of Molecular Biology in Medical Sciences; the Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou 310009, Zhejiang Province, China
| | - Jiawei Zhang
- Cancer Institute, Key Laboratory of Cancer Prevention & Intervention, China National Ministry of Education; Key Laboratory of Molecular Biology in Medical Sciences; the Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou 310009, Zhejiang Province, China
| | - Ying Gu
- Institute of genetics, Zhejiang University, Zijingang Campus of Zhejiang University, Yuhangtang Road No.388, Hangzhou, 310058, Zhejiang Province, China
| | - Shu Zheng
- Cancer Institute, Key Laboratory of Cancer Prevention & Intervention, China National Ministry of Education; Key Laboratory of Molecular Biology in Medical Sciences; the Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou 310009, Zhejiang Province, China
| | - Weiting Ge
- Cancer Institute, Key Laboratory of Cancer Prevention & Intervention, China National Ministry of Education; Key Laboratory of Molecular Biology in Medical Sciences; the Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou 310009, Zhejiang Province, China.,Cancer Center, Zhejiang University, Hangzhou, 310000, Zhejiang Province, China
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Regensburger D, Tenkerian C, Pürzer V, Schmid B, Wohlfahrt T, Stolzer I, López-Posadas R, Günther C, Waldner MJ, Becker C, Sticht H, Petter K, Flierl C, Gass T, Thoenissen T, Geppert CI, Britzen-Laurent N, Méniel VS, Ramming A, Stürzl M, Naschberger E. Matricellular Protein SPARCL1 Regulates Blood Vessel Integrity and Antagonizes Inflammatory Bowel Disease. Inflamm Bowel Dis 2021; 27:1491-1502. [PMID: 33393634 PMCID: PMC8376124 DOI: 10.1093/ibd/izaa346] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND The understanding of vascular plasticity is key to defining the role of blood vessels in physiologic and pathogenic processes. In the present study, the impact of the vascular quiescence marker SPARCL1 on angiogenesis, capillary morphogenesis, and vessel integrity was evaluated. METHODS Angiogenesis was studied using the metatarsal test, an ex vivo model of sprouting angiogenesis. In addition, acute and chronic dextran sodium sulfate colitis models with SPARCL1 knockout mice were applied. RESULTS This approach indicated that SPARCL1 inhibits angiogenesis and supports vessel morphogenesis and integrity. Evidence was provided that SPARCL1-mediated stabilization of vessel integrity counteracts vessel permeability and inflammation in acute and chronic dextran sodium sulfate colitis models. Structure-function analyses of purified SPARCL1 identified the acidic domain of the protein necessary for its anti-angiogenic activity. CONCLUSIONS Our findings inaugurate SPARCL1 as a blood vessel-derived anti-angiogenic molecule required for vessel morphogenesis and integrity. SPARCL1 opens new perspectives as a vascular marker of susceptibility to colitis and as a therapeutic molecule to support blood vessel stability in this disease.
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Affiliation(s)
- Daniela Regensburger
- Division of Molecular and Experimental Surgery, Translational Research Center, Department of Surgery, University Medical Center Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Clara Tenkerian
- Division of Molecular and Experimental Surgery, Translational Research Center, Department of Surgery, University Medical Center Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Victoria Pürzer
- Division of Molecular and Experimental Surgery, Translational Research Center, Department of Surgery, University Medical Center Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Benjamin Schmid
- Optical Imaging Centre, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Thomas Wohlfahrt
- Department of Internal Medicine 3, Rheumatology and Immunology, University Medical Center Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Iris Stolzer
- Department of Medicine 1, Gastroenterology, Pneumology and Endocrinology, University Medical Center Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Rocío López-Posadas
- Department of Medicine 1, Gastroenterology, Pneumology and Endocrinology, University Medical Center Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Claudia Günther
- Department of Medicine 1, Gastroenterology, Pneumology and Endocrinology, University Medical Center Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Maximilian J Waldner
- Department of Medicine 1, Gastroenterology, Pneumology and Endocrinology, University Medical Center Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Christoph Becker
- Department of Medicine 1, Gastroenterology, Pneumology and Endocrinology, University Medical Center Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Heinrich Sticht
- Division of Bioinformatics, Institute of Biochemistry, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Katja Petter
- Division of Molecular and Experimental Surgery, Translational Research Center, Department of Surgery, University Medical Center Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Christian Flierl
- Division of Molecular and Experimental Surgery, Translational Research Center, Department of Surgery, University Medical Center Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Tobias Gass
- Division of Molecular and Experimental Surgery, Translational Research Center, Department of Surgery, University Medical Center Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Tim Thoenissen
- Division of Molecular and Experimental Surgery, Translational Research Center, Department of Surgery, University Medical Center Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Carol I Geppert
- Institute of Pathology, University Medical Center Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Nathalie Britzen-Laurent
- Division of Molecular and Experimental Surgery, Translational Research Center, Department of Surgery, University Medical Center Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Valérie S Méniel
- European Cancer Stem Cell Research Institute, Cardiff University, Cardiff, United Kingdom
| | - Andreas Ramming
- Department of Internal Medicine 3, Rheumatology and Immunology, University Medical Center Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Michael Stürzl
- Division of Molecular and Experimental Surgery, Translational Research Center, Department of Surgery, University Medical Center Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Elisabeth Naschberger
- Division of Molecular and Experimental Surgery, Translational Research Center, Department of Surgery, University Medical Center Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
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Stürzl M, Kunz M, Krug SM, Naschberger E. Angiocrine Regulation of Epithelial Barrier Integrity in Inflammatory Bowel Disease. Front Med (Lausanne) 2021; 8:643607. [PMID: 34409045 PMCID: PMC8365087 DOI: 10.3389/fmed.2021.643607] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 07/07/2021] [Indexed: 12/16/2022] Open
Abstract
Inflammatory bowel disease describes chronic inflammatory disorders. The incidence of the disease is rising. A major step in disease development is the breakdown of the epithelial cell barrier. Numerous blood vessels are directly located underneath this barrier. Diseased tissues are heavily vascularized and blood vessels significantly contribute to disease progression. The gut-vascular barrier (GVB) is an additional barrier controlling the entry of substances into the portal circulation and to the liver after passing the first epithelial barrier. The presence of the GVB rises the question, whether the vascular and endothelial barriers may communicate bi-directionally in the regulation of selective barrier permeability. Communication from epithelial to endothelial cells is well-accepted. In contrast, little is known on the respective backwards communication. Only recently, perfusion-independent angiocrine functions of endothelial cells were recognized in a way that endothelial cells release specific soluble factors that may directly act on the epithelial barrier. This review discusses the putative involvement of angiocrine inter-barrier communication in the pathogenesis of IBD.
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Affiliation(s)
- Michael Stürzl
- Division of Molecular and Experimental Surgery, Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander University (FAU) of Erlangen-Nürnberg, Erlangen, Germany
| | - Meik Kunz
- Chair of Medical Informatics, Friedrich-Alexander-University (FAU) of Erlangen-Nürnberg, Erlangen, and Fraunhofer Institute of Toxicology and Experimental Medicine, Hannover, Germany
| | - Susanne M. Krug
- Clinical Physiology/Nutritional Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Elisabeth Naschberger
- Division of Molecular and Experimental Surgery, Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander University (FAU) of Erlangen-Nürnberg, Erlangen, Germany
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Sreekanth V, Kar A, Kumar S, Pal S, Yadav P, Sharma Y, Komalla V, Sharma H, Shyam R, Sharma RD, Mukhopadhyay A, Sengupta S, Dasgupta U, Bajaj A. Bile Acid Tethered Docetaxel-Based Nanomicelles Mitigate Tumor Progression through Epigenetic Changes. Angew Chem Int Ed Engl 2021; 60:5394-5399. [PMID: 33258265 DOI: 10.1002/anie.202015173] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Indexed: 12/18/2022]
Abstract
In this study, we describe the engineering of sub-100 nm nanomicelles (DTX-PC NMs) derived from phosphocholine derivative of docetaxel (DTX)-conjugated lithocholic acid (DTX-PC) and poly(ethylene glycol)-tethered lithocholic acid. Administration of DTX-PC NMs decelerate tumor progression and increase the mice survivability compared to Taxotere (DTX-TS), the FDA-approved formulation of DTX. Unlike DTX-TS, DTX-PC NMs do not cause any systemic toxicity and slow the decay rate of plasma DTX concentration in rodents and non-rodent species including non-human primates. We further demonstrate that DTX-PC NMs target demethylation of CpG islands of Sparcl1 (a tumor suppressor gene) by suppressing DNA methyltransferase activity and increase the expression of Sparcl1 that leads to tumor regression. Therefore, this unique system has the potential to improve the quality of life in cancer patients and can be translated as a next-generation chemotherapeutic.
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Affiliation(s)
- Vedagopuram Sreekanth
- Laboratory of Nanotechnology and Chemical Biology, Regional Centre for Biotechnology, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, 121001, Haryana, India
- Current address: Brigham and Women's Hospital, Division of Renal Medicine and Engineering, Boston, MA, 02115, USA
| | - Animesh Kar
- Laboratory of Nanotechnology and Chemical Biology, Regional Centre for Biotechnology, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, 121001, Haryana, India
| | - Sandeep Kumar
- Laboratory of Nanotechnology and Chemical Biology, Regional Centre for Biotechnology, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, 121001, Haryana, India
| | - Sanjay Pal
- Laboratory of Nanotechnology and Chemical Biology, Regional Centre for Biotechnology, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, 121001, Haryana, India
| | - Poonam Yadav
- Laboratory of Nanotechnology and Chemical Biology, Regional Centre for Biotechnology, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, 121001, Haryana, India
| | - Yamini Sharma
- Laboratory of Nanotechnology and Chemical Biology, Regional Centre for Biotechnology, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, 121001, Haryana, India
| | - Varsha Komalla
- Laboratory of Nanotechnology and Chemical Biology, Regional Centre for Biotechnology, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, 121001, Haryana, India
- Current address: Graduate School of Health, University of Technology, Sydney, Building 20, 100-102 Broadway, Chippendale, NSW, 2008, Australia
| | - Harsh Sharma
- Amity Institute of Integrative Sciences and Health, Amity University Haryana, Panchgaon, Manesar, Gurgaon, 122413, Haryana, India
| | - Radhey Shyam
- National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, 110067, India
| | - Ravi Datta Sharma
- Amity Institute of Integrative Sciences and Health, Amity University Haryana, Panchgaon, Manesar, Gurgaon, 122413, Haryana, India
| | - Arnab Mukhopadhyay
- National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, 110067, India
| | - Sagar Sengupta
- National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, 110067, India
| | - Ujjaini Dasgupta
- Amity Institute of Integrative Sciences and Health, Amity University Haryana, Panchgaon, Manesar, Gurgaon, 122413, Haryana, India
| | - Avinash Bajaj
- Laboratory of Nanotechnology and Chemical Biology, Regional Centre for Biotechnology, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, 121001, Haryana, India
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Sreekanth V, Kar A, Kumar S, Pal S, Yadav P, Sharma Y, Komalla V, Sharma H, Shyam R, Sharma RD, Mukhopadhyay A, Sengupta S, Dasgupta U, Bajaj A. Bile Acid Tethered Docetaxel‐Based Nanomicelles Mitigate Tumor Progression through Epigenetic Changes. Angew Chem Int Ed Engl 2021. [DOI: 10.1002/ange.202015173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Vedagopuram Sreekanth
- Laboratory of Nanotechnology and Chemical Biology Regional Centre for Biotechnology NCR Biotech Science Cluster 3rd Milestone, Faridabad-Gurgaon Expressway Faridabad 121001 Haryana India
- Current address: Brigham and Women's Hospital Division of Renal Medicine and Engineering Boston MA 02115 USA
| | - Animesh Kar
- Laboratory of Nanotechnology and Chemical Biology Regional Centre for Biotechnology NCR Biotech Science Cluster 3rd Milestone, Faridabad-Gurgaon Expressway Faridabad 121001 Haryana India
| | - Sandeep Kumar
- Laboratory of Nanotechnology and Chemical Biology Regional Centre for Biotechnology NCR Biotech Science Cluster 3rd Milestone, Faridabad-Gurgaon Expressway Faridabad 121001 Haryana India
| | - Sanjay Pal
- Laboratory of Nanotechnology and Chemical Biology Regional Centre for Biotechnology NCR Biotech Science Cluster 3rd Milestone, Faridabad-Gurgaon Expressway Faridabad 121001 Haryana India
| | - Poonam Yadav
- Laboratory of Nanotechnology and Chemical Biology Regional Centre for Biotechnology NCR Biotech Science Cluster 3rd Milestone, Faridabad-Gurgaon Expressway Faridabad 121001 Haryana India
| | - Yamini Sharma
- Laboratory of Nanotechnology and Chemical Biology Regional Centre for Biotechnology NCR Biotech Science Cluster 3rd Milestone, Faridabad-Gurgaon Expressway Faridabad 121001 Haryana India
| | - Varsha Komalla
- Laboratory of Nanotechnology and Chemical Biology Regional Centre for Biotechnology NCR Biotech Science Cluster 3rd Milestone, Faridabad-Gurgaon Expressway Faridabad 121001 Haryana India
- Current address: Graduate School of Health University of Technology, Sydney, Building 20 100–102 Broadway Chippendale NSW 2008 Australia
| | - Harsh Sharma
- Amity Institute of Integrative Sciences and Health Amity University Haryana Panchgaon, Manesar Gurgaon 122413 Haryana India
| | - Radhey Shyam
- National Institute of Immunology Aruna Asaf Ali Marg New Delhi 110067 India
| | - Ravi Datta Sharma
- Amity Institute of Integrative Sciences and Health Amity University Haryana Panchgaon, Manesar Gurgaon 122413 Haryana India
| | - Arnab Mukhopadhyay
- National Institute of Immunology Aruna Asaf Ali Marg New Delhi 110067 India
| | - Sagar Sengupta
- National Institute of Immunology Aruna Asaf Ali Marg New Delhi 110067 India
| | - Ujjaini Dasgupta
- Amity Institute of Integrative Sciences and Health Amity University Haryana Panchgaon, Manesar Gurgaon 122413 Haryana India
| | - Avinash Bajaj
- Laboratory of Nanotechnology and Chemical Biology Regional Centre for Biotechnology NCR Biotech Science Cluster 3rd Milestone, Faridabad-Gurgaon Expressway Faridabad 121001 Haryana India
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Interleukin-3 is a predictive marker for severity and outcome during SARS-CoV-2 infections. Nat Commun 2021; 12:1112. [PMID: 33602937 PMCID: PMC7893044 DOI: 10.1038/s41467-021-21310-4] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 01/19/2021] [Indexed: 12/11/2022] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a worldwide health threat. In a prospective multicentric study, we identify IL-3 as an independent prognostic marker for the outcome during SARS-CoV-2 infections. Specifically, low plasma IL-3 levels is associated with increased severity, viral load, and mortality during SARS-CoV-2 infections. Patients with severe COVID-19 exhibit also reduced circulating plasmacytoid dendritic cells (pDCs) and low plasma IFNα and IFNλ levels when compared to non-severe COVID-19 patients. In a mouse model of pulmonary HSV-1 infection, treatment with recombinant IL-3 reduces viral load and mortality. Mechanistically, IL-3 increases innate antiviral immunity by promoting the recruitment of circulating pDCs into the airways by stimulating CXCL12 secretion from pulmonary CD123+ epithelial cells, both, in mice and in COVID-19 negative patients exhibiting pulmonary diseases. This study identifies IL-3 as a predictive disease marker for SARS-CoV-2 infections and as a potential therapeutic target for pulmunory viral infections. Here, the authors identify interleukin-3 as a predictive marker for severity and outcome of SARS-CoV-2 infection in a multi-center, prospective study and find that patients with severe COVID-19 have reduced circulating plasmacytoid dendritic cell levels compared to non-severe COVID-19 patients.
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Wang H, Feng C, Lu M, Zhang B, Xu Y, Zeng Q, Xi J, Zhou J, Ying X, Zhang J, Yue W, Pei X. Integrative single-cell transcriptome analysis reveals a subpopulation of fibroblasts associated with favorable prognosis of liver cancer patients. Transl Oncol 2021; 14:100981. [PMID: 33395744 PMCID: PMC7719961 DOI: 10.1016/j.tranon.2020.100981] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 11/23/2020] [Accepted: 11/30/2020] [Indexed: 01/11/2023] Open
Abstract
Single-cell transcriptome analysis has provided detailed insights into the ecosystem of liver cancer. However, the changes of the cellular and molecular components of liver tumors in comparison with normal livers have not been described at single-cell level. Here, we performed an integrative single-cell analysis of both normal livers and liver cancers. Principal component analysis was firstly performed to delineate the cell lineages in liver tissues. Differential gene expression within major cell types were then analyzed between tumor and normal samples, thus resolved the cell type-specific molecular alterations in liver cancer development. Moreover, a comparison between liver cancer derived versus normal liver derived cell components revealed that two subpopulations of fibroblasts were exclusively expanded in liver cancer tissues. By further defining subpopulation-specific gene signatures, characterizing their spatial distribution in tumor tissues and investigating their clinical significance, we found that the SPARCL1 positive fibroblasts, representing a group of tumor vessel associated fibroblasts, were related to reduced vascular invasion and prolonged survival of liver cancer patients. Through establishing an in-vitro endothelial-to-mesenchymal transition model, we verified the conversion of the fetal liver sinusoidal endothelial cells into the fibroblast-like cells, demonstrating a possible endothelial cell origination of the SPARCL1 positive fibroblasts. Our study provides new insights into the cell atlas alteration, especially the expanded fibroblasts in liver cancers.
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Affiliation(s)
- Haiyang Wang
- Stem Cell and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Beijing 100850, China; South China Research Center for Stem Cell & Regenerative Medicine, SCIB, Guangzhou 510005, China
| | - Chao Feng
- Institute of Military Cognition and Brain Sciences, Academy of Military Medical Sciences, Beijing 100850, China
| | - Meixin Lu
- Stem Cell and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Beijing 100850, China; South China Research Center for Stem Cell & Regenerative Medicine, SCIB, Guangzhou 510005, China
| | - Biao Zhang
- Stem Cell and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Beijing 100850, China; South China Research Center for Stem Cell & Regenerative Medicine, SCIB, Guangzhou 510005, China
| | - Yingchen Xu
- Department of Hepatobiliary Surgery, Beijing Tongren Hospital, Beijing 100730, China
| | - Quan Zeng
- Stem Cell and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Beijing 100850, China; South China Research Center for Stem Cell & Regenerative Medicine, SCIB, Guangzhou 510005, China
| | - Jiafei Xi
- Stem Cell and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Beijing 100850, China; South China Research Center for Stem Cell & Regenerative Medicine, SCIB, Guangzhou 510005, China
| | - Junnian Zhou
- Stem Cell and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Beijing 100850, China; South China Research Center for Stem Cell & Regenerative Medicine, SCIB, Guangzhou 510005, China; Experimental Hematology and Biochemistry Lab, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Xiaomin Ying
- Institute of Military Cognition and Brain Sciences, Academy of Military Medical Sciences, Beijing 100850, China
| | - Jian Zhang
- Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin 300072, China.
| | - Wen Yue
- Stem Cell and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Beijing 100850, China; South China Research Center for Stem Cell & Regenerative Medicine, SCIB, Guangzhou 510005, China.
| | - Xuetao Pei
- Stem Cell and Regenerative Medicine Lab, Institute of Health Service and Transfusion Medicine, Beijing 100850, China; South China Research Center for Stem Cell & Regenerative Medicine, SCIB, Guangzhou 510005, China.
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Niland S, Eble JA. Hold on or Cut? Integrin- and MMP-Mediated Cell-Matrix Interactions in the Tumor Microenvironment. Int J Mol Sci 2020; 22:ijms22010238. [PMID: 33379400 PMCID: PMC7794804 DOI: 10.3390/ijms22010238] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 12/21/2020] [Accepted: 12/23/2020] [Indexed: 02/07/2023] Open
Abstract
The tumor microenvironment (TME) has become the focus of interest in cancer research and treatment. It includes the extracellular matrix (ECM) and ECM-modifying enzymes that are secreted by cancer and neighboring cells. The ECM serves both to anchor the tumor cells embedded in it and as a means of communication between the various cellular and non-cellular components of the TME. The cells of the TME modify their surrounding cancer-characteristic ECM. This in turn provides feedback to them via cellular receptors, thereby regulating, together with cytokines and exosomes, differentiation processes as well as tumor progression and spread. Matrix remodeling is accomplished by altering the repertoire of ECM components and by biophysical changes in stiffness and tension caused by ECM-crosslinking and ECM-degrading enzymes, in particular matrix metalloproteinases (MMPs). These can degrade ECM barriers or, by partial proteolysis, release soluble ECM fragments called matrikines, which influence cells inside and outside the TME. This review examines the changes in the ECM of the TME and the interaction between cells and the ECM, with a particular focus on MMPs.
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Huang N, Liu Y, Fang Y, Zheng S, Wu J, Wang M, Zhong W, Shi M, Xing M, Liao W. Gold Nanoparticles Induce Tumor Vessel Normalization and Impair Metastasis by Inhibiting Endothelial Smad2/3 Signaling. ACS NANO 2020; 14:7940-7958. [PMID: 32413258 DOI: 10.1021/acsnano.9b08460] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Gold nanoparticles (AuNPs) are a promising nanomaterial due to their drug-delivery properties and inherent anti-neoplastic activity. Here, we focused on the anti-neoplastic effects of an improved targeting polymer and folic acid-modified gold nanoparticles (AuNPP-FA) without therapeutic drugs. AuNPP-FA inhibited tumor proliferation both in vitro and in vivo, and tumor metastasis was controlled in vivo. We also found that, in addition to inhibiting tumor angiogenesis, AuNPP-FA normalized tumor vasculature by increasing pericyte coverage and strengthening tight junctions by upregulating VE-cadherin (VE-cad) levels on endothelial cells. This decreased vascular permeability, improved vascular perfusion, and alleviated tissue hypoxia. The immunotherapeutic response was enhanced due to the increased infiltration of CD3+CD8+ T lymphocytes. AuNPP-FA increased the expression and secretion of semaphorin 3A (SEMA3A) in cancer cells to further inhibit Smad2/3 signaling in human umbilical vein endothelial cells (HUVECs). This normalized tumor vasculature and inhibited metastasis. In conclusion, AuNPP-FA normalized tumor vasculature; therefore, AuNPP-FA has great potential for future clinical applications.
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Affiliation(s)
- Na Huang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People's Republic of China
| | - Yuqing Liu
- Department of Mechanical Engineering, Faculty of Agriculture, University of Manitoba, Winnipeg R3T2N2, Canada
| | - Yisheng Fang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People's Republic of China
| | - Siting Zheng
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People's Republic of China
| | - Jianhua Wu
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People's Republic of China
| | - Miaohong Wang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People's Republic of China
| | - Wen Zhong
- Department of Biosystem Engineering, Faculty of Agriculture, University of Manitoba, Winnipeg R3T2N2, Canada
| | - Min Shi
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People's Republic of China
| | - Malcolm Xing
- Department of Mechanical Engineering, Faculty of Agriculture, University of Manitoba, Winnipeg R3T2N2, Canada
| | - Wangjun Liao
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People's Republic of China
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Andreuzzi E, Capuano A, Poletto E, Pivetta E, Fejza A, Favero A, Doliana R, Cannizzaro R, Spessotto P, Mongiat M. Role of Extracellular Matrix in Gastrointestinal Cancer-Associated Angiogenesis. Int J Mol Sci 2020; 21:E3686. [PMID: 32456248 PMCID: PMC7279269 DOI: 10.3390/ijms21103686] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 05/20/2020] [Accepted: 05/21/2020] [Indexed: 02/07/2023] Open
Abstract
Gastrointestinal tumors are responsible for more cancer-related fatalities than any other type of tumors, and colorectal and gastric malignancies account for a large part of these diseases. Thus, there is an urgent need to develop new therapeutic approaches to improve the patients' outcome and the tumor microenvironment is a promising arena for the development of such treatments. In fact, the nature of the microenvironment in the different gastrointestinal tracts may significantly influence not only tumor development but also the therapy response. In particular, an important microenvironmental component and a potential therapeutic target is the vasculature. In this context, the extracellular matrix is a key component exerting an active effect in all the hallmarks of cancer, including angiogenesis. Here, we summarized the current knowledge on the role of extracellular matrix in affecting endothelial cell function and intratumoral vascularization in the context of colorectal and gastric cancer. The extracellular matrix acts both directly on endothelial cells and indirectly through its remodeling and the consequent release of growth factors. We envision that a deeper understanding of the role of extracellular matrix and of its remodeling during cancer progression is of chief importance for the development of new, more efficacious, targeted therapies.
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Affiliation(s)
- Eva Andreuzzi
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (E.A.); (A.C.); (E.P.); (E.P.); (A.F.); (A.F.); (R.D.); (P.S.)
| | - Alessandra Capuano
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (E.A.); (A.C.); (E.P.); (E.P.); (A.F.); (A.F.); (R.D.); (P.S.)
| | - Evelina Poletto
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (E.A.); (A.C.); (E.P.); (E.P.); (A.F.); (A.F.); (R.D.); (P.S.)
| | - Eliana Pivetta
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (E.A.); (A.C.); (E.P.); (E.P.); (A.F.); (A.F.); (R.D.); (P.S.)
| | - Albina Fejza
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (E.A.); (A.C.); (E.P.); (E.P.); (A.F.); (A.F.); (R.D.); (P.S.)
| | - Andrea Favero
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (E.A.); (A.C.); (E.P.); (E.P.); (A.F.); (A.F.); (R.D.); (P.S.)
| | - Roberto Doliana
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (E.A.); (A.C.); (E.P.); (E.P.); (A.F.); (A.F.); (R.D.); (P.S.)
| | - Renato Cannizzaro
- Department of Clinical Oncology, Experimental Gastrointestinal Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy;
| | - Paola Spessotto
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (E.A.); (A.C.); (E.P.); (E.P.); (A.F.); (A.F.); (R.D.); (P.S.)
| | - Maurizio Mongiat
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (E.A.); (A.C.); (E.P.); (E.P.); (A.F.); (A.F.); (R.D.); (P.S.)
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Klingler A, Regensburger D, Tenkerian C, Britzen-Laurent N, Hartmann A, Stürzl M, Naschberger E. Species-, organ- and cell-type-dependent expression of SPARCL1 in human and mouse tissues. PLoS One 2020; 15:e0233422. [PMID: 32437418 PMCID: PMC7241726 DOI: 10.1371/journal.pone.0233422] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Accepted: 05/05/2020] [Indexed: 12/30/2022] Open
Abstract
SPARCL1 is a matricellular protein with anti-adhesive, anti-proliferative and anti-tumorigenic functions and is frequently downregulated in tumors such as colorectal carcinoma or non-small cell lung cancer. Studies have identified SPARCL1 as an angiocrine tumor suppressor secreted by tumor vessel endothelial cells, thereby exerting inhibitory activity on angiogenesis and tumor growth, in colorectal carcinoma. It is unknown whether SPARCL1 may exert these homeostatic functions in all organs and in other species. Therefore, SPARCL1 expression was comparatively analysed between humans and mice in a systematic manner. Murine Sparcl1 (mSparcl1) is most strongly expressed in the lung; expressed at an intermediate level in most organs, including the large intestine; and absent in the liver. In human tissues, SPARCL1 (hSPARCL1) was detected in all organs, with the strongest expression in the stomach, large intestine and lung, mostly consistent with the murine expression pattern. A striking difference between human and murine tissues was the absence of mSparcl1 expression in murine livers, while human livers showed moderate expression. Furthermore, mSparcl1 was predominantly associated with mural cells, whereas hSPARCL1 was detected in both mural and endothelial cells. Human SPARCL1 expression was downregulated in different carcinomas, including lung and colon cancers. In conclusion, this study revealed species-, organ- and cell-type-dependent expression of SPARCL1, suggesting that its function may not be similar between humans and mice.
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Affiliation(s)
- Anika Klingler
- Division of Molecular and Experimental Surgery, Department of Surgery, University Medical Center Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg, Translational Research Center, Erlangen, Germany
| | - Daniela Regensburger
- Division of Molecular and Experimental Surgery, Department of Surgery, University Medical Center Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg, Translational Research Center, Erlangen, Germany
| | - Clara Tenkerian
- Division of Molecular and Experimental Surgery, Department of Surgery, University Medical Center Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg, Translational Research Center, Erlangen, Germany
| | - Nathalie Britzen-Laurent
- Division of Molecular and Experimental Surgery, Department of Surgery, University Medical Center Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg, Translational Research Center, Erlangen, Germany
| | - Arndt Hartmann
- Institute of Pathology, University Medical Center Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany
| | - Michael Stürzl
- Division of Molecular and Experimental Surgery, Department of Surgery, University Medical Center Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg, Translational Research Center, Erlangen, Germany
| | - Elisabeth Naschberger
- Division of Molecular and Experimental Surgery, Department of Surgery, University Medical Center Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg, Translational Research Center, Erlangen, Germany
- * E-mail:
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47
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Yorozu A, Yamamoto E, Niinuma T, Tsuyada A, Maruyama R, Kitajima H, Numata Y, Kai M, Sudo G, Kubo T, Nishidate T, Okita K, Takemasa I, Nakase H, Sugai T, Takano K, Suzuki H. Upregulation of adipocyte enhancer-binding protein 1 in endothelial cells promotes tumor angiogenesis in colorectal cancer. Cancer Sci 2020; 111:1631-1644. [PMID: 32086986 PMCID: PMC7226196 DOI: 10.1111/cas.14360] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 02/08/2020] [Accepted: 02/16/2020] [Indexed: 02/06/2023] Open
Abstract
Tumor angiogenesis is an important therapeutic target in colorectal cancer (CRC). We aimed to identify novel genes associated with angiogenesis in CRC. Using RNA sequencing analysis in normal and tumor endothelial cells (TECs) isolated from primary CRC tissues, we detected frequent upregulation of adipocyte enhancer‐binding protein 1 (AEBP1) in TECs. Immunohistochemical analysis revealed that AEBP1 is upregulated in TECs and stromal cells in CRC tissues. Quantitative RT‐PCR analysis showed that there is little or no AEBP1 expression in CRC cell lines, but that AEBP1 is well expressed in vascular endothelial cells. Levels of AEBP1 expression in Human umbilical vein endothelial cells (HUVECs) were upregulated by tumor conditioned medium derived from CRC cells or by direct coculture with CRC cells. Knockdown of AEBP1 suppressed proliferation, migration, and in vitro tube formation by HUVECs. In xenograft experiments, AEBP1 knockdown suppressed tumorigenesis and microvessel formation. Depletion of AEBP1 in HUVECs downregulated a series of genes associated with angiogenesis or endothelial function, including aquaporin 1 (AQP1) and periostin (POSTN), suggesting that AEBP1 might promote angiogenesis through regulation of those genes. These results suggest that upregulation of AEBP1 contributes to tumor angiogenesis in CRC, which makes AEBP1 a potentially useful therapeutic target.
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Affiliation(s)
- Akira Yorozu
- Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan.,Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Eiichiro Yamamoto
- Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan.,Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Takeshi Niinuma
- Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Akihiro Tsuyada
- Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Reo Maruyama
- Project for Cancer Epigenomics, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Hiroshi Kitajima
- Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Yuto Numata
- Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Masahiro Kai
- Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Gota Sudo
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Toshiyuki Kubo
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Toshihiko Nishidate
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Kenji Okita
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Ichiro Takemasa
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hiroshi Nakase
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Tamotsu Sugai
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Kenichi Takano
- Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hiromu Suzuki
- Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan
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48
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Rohlenova K, Goveia J, García-Caballero M, Subramanian A, Kalucka J, Treps L, Falkenberg KD, de Rooij LPMH, Zheng Y, Lin L, Sokol L, Teuwen LA, Geldhof V, Taverna F, Pircher A, Conradi LC, Khan S, Stegen S, Panovska D, De Smet F, Staal FJT, Mclaughlin RJ, Vinckier S, Van Bergen T, Ectors N, De Haes P, Wang J, Bolund L, Schoonjans L, Karakach TK, Yang H, Carmeliet G, Liu Y, Thienpont B, Dewerchin M, Eelen G, Li X, Luo Y, Carmeliet P. Single-Cell RNA Sequencing Maps Endothelial Metabolic Plasticity in Pathological Angiogenesis. Cell Metab 2020; 31:862-877.e14. [PMID: 32268117 DOI: 10.1016/j.cmet.2020.03.009] [Citation(s) in RCA: 199] [Impact Index Per Article: 39.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 12/20/2019] [Accepted: 03/09/2020] [Indexed: 01/22/2023]
Abstract
Endothelial cell (EC) metabolism is an emerging target for anti-angiogenic therapy in tumor angiogenesis and choroidal neovascularization (CNV), but little is known about individual EC metabolic transcriptomes. By single-cell RNA sequencing 28,337 murine choroidal ECs (CECs) and sprouting CNV-ECs, we constructed a taxonomy to characterize their heterogeneity. Comparison with murine lung tumor ECs (TECs) revealed congruent marker gene expression by distinct EC phenotypes across tissues and diseases, suggesting similar angiogenic mechanisms. Trajectory inference predicted that differentiation of venous to angiogenic ECs was accompanied by metabolic transcriptome plasticity. ECs displayed metabolic transcriptome heterogeneity during cell-cycle progression and in quiescence. Hypothesizing that conserved genes are important, we used an integrated analysis, based on congruent transcriptome analysis, CEC-tailored genome-scale metabolic modeling, and gene expression meta-analysis in cross-species datasets, followed by in vitro and in vivo validation, to identify SQLE and ALDH18A1 as previously unknown metabolic angiogenic targets.
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Affiliation(s)
- Katerina Rohlenova
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium
| | - Jermaine Goveia
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium
| | - Melissa García-Caballero
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium
| | - Abhishek Subramanian
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium
| | - Joanna Kalucka
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium
| | - Lucas Treps
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium
| | - Kim D Falkenberg
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium
| | - Laura P M H de Rooij
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium
| | - Yingfeng Zheng
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, Guangdong, China
| | - Lin Lin
- Department of Biomedicine, Aarhus University, Aarhus 8000, Denmark; Lars Bolund Institute of Regenerative Medicine, BGI-Qingdao, Qingdao 266555, China
| | - Liliana Sokol
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium
| | - Laure-Anne Teuwen
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium; Translational Cancer Research Unit, GZA Hospitals Sint-Augustinus, Antwerp 2610, Belgium; Center for Oncological Research, University of Antwerp, Antwerp 2000, Belgium
| | - Vincent Geldhof
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium
| | - Federico Taverna
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium
| | - Andreas Pircher
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium
| | - Lena-Christin Conradi
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium
| | - Shawez Khan
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium
| | - Steve Stegen
- Laboratory of Clinical and Experimental Endocrinology, Department of Chronic Diseases, Metabolism and Aging, KU Leuven, Leuven 3000, Belgium
| | - Dena Panovska
- Laboratory for Precision Cancer Medicine, Translational Cell & Tissue Research, Department of Imaging & Pathology, KU Leuven, Leuven 3000, Belgium
| | - Frederik De Smet
- Laboratory for Precision Cancer Medicine, Translational Cell & Tissue Research, Department of Imaging & Pathology, KU Leuven, Leuven 3000, Belgium
| | - Frank J T Staal
- Department of Immunology and Blood Transfusion, Leiden University Medical Center, Leiden 2300 RC, the Netherlands
| | - Rene J Mclaughlin
- Department of Immunology and Blood Transfusion, Leiden University Medical Center, Leiden 2300 RC, the Netherlands
| | - Stefan Vinckier
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium
| | | | - Nadine Ectors
- Laboratory for Precision Cancer Medicine, Translational Cell & Tissue Research, Department of Imaging & Pathology, KU Leuven, Leuven 3000, Belgium
| | | | - Jian Wang
- BGI-Shenzhen, Shenzhen 518083, China; China National GeneBank, BGI-Shenzhen, Shenzhen 518120, China
| | - Lars Bolund
- Department of Biomedicine, Aarhus University, Aarhus 8000, Denmark; Lars Bolund Institute of Regenerative Medicine, BGI-Qingdao, Qingdao 266555, China
| | - Luc Schoonjans
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, Guangdong, China
| | - Tobias K Karakach
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium
| | - Huanming Yang
- BGI-Shenzhen, Shenzhen 518083, China; China National GeneBank, BGI-Shenzhen, Shenzhen 518120, China
| | - Geert Carmeliet
- Laboratory of Clinical and Experimental Endocrinology, Department of Chronic Diseases, Metabolism and Aging, KU Leuven, Leuven 3000, Belgium
| | - Yizhi Liu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, Guangdong, China
| | - Bernard Thienpont
- Laboratory for Functional Epigenetics, Department of Human Genetics, KU Leuven, Leuven 3000, Belgium
| | - Mieke Dewerchin
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium
| | - Guy Eelen
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium
| | - Xuri Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, Guangdong, China.
| | - Yonglun Luo
- Department of Biomedicine, Aarhus University, Aarhus 8000, Denmark; Lars Bolund Institute of Regenerative Medicine, BGI-Qingdao, Qingdao 266555, China; BGI-Shenzhen, Shenzhen 518083, China; China National GeneBank, BGI-Shenzhen, Shenzhen 518120, China.
| | - Peter Carmeliet
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, Guangdong, China.
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49
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Carbotti G, Petretto A, Naschberger E, Stürzl M, Martini S, Mingari MC, Filaci G, Ferrini S, Fabbi M. Cytokine-Induced Guanylate Binding Protein 1 (GBP1) Release from Human Ovarian Cancer Cells. Cancers (Basel) 2020; 12:E488. [PMID: 32093058 PMCID: PMC7072386 DOI: 10.3390/cancers12020488] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 02/08/2020] [Accepted: 02/17/2020] [Indexed: 01/01/2023] Open
Abstract
We showed that IL-27 shares several effects with IFN-γ in human cancer cells. To identify novel extracellular mediators, potentially involved in epithelial ovarian cancer (EOC) biology, we analyzed the effect of IL-27 or IFN-γ on the secretome of cultured EOC cells by mass-spectrometry (nano-UHPLC-MS/MS). IL-27 and IFN-γ modulate the release of a limited fraction of proteins among those induced in the whole cell. We focused our attention on GBP1, a guanylate-binding protein and GTPase, which mediates several biological activities of IFNs. Cytokine treatment induced GBP1, 2, and 5 expressions in EOC cells, but only GBP1 was secreted. ELISA and immunoblotting showed that cytokine-stimulated EOC cells release full-length GBP1 in vitro, through non-classical pathways, not involving microvesicles. Importantly, full-length GBP1 accumulates in the ascites of most EOC patients and ex-vivo EOC cells show constitutive tyrosine-phosphorylated STAT1/3 proteins and GBP1 expression, supporting a role for Signal Transducer And Activator Of Transcription (STAT)-activating cytokines in vivo. High GBP1 gene expression correlates with better overall survival in the TCGA (The Cancer Genome Atlas) dataset of EOC. In addition, GBP1 transfection partially reduced EOC cell viability in an MTT assay. Our data show for the first time that cytokine-stimulated tumor cells release soluble GBP1 in vitro and in vivo and suggest that GBP1 may have anti-tumor effects in EOC.
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Affiliation(s)
- Grazia Carbotti
- IRCCS Ospedale Policlinico San Martino, Biotherapies Unit, Largo R. Benzi 10, 16132 Genoa, Italy; (G.C.); (G.F.)
| | - Andrea Petretto
- Core Facilities—Clinical Proteomics and Metabolomics, IRCCS Istituto Giannina Gaslini, Via Gerolamo Gaslini 5, 16147 Genoa, Italy;
| | - Elisabeth Naschberger
- Division of Molecular and Experimental Surgery, University Medical Center Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Schwabachanlage 12, 91054 Erlangen, Germany; (E.N.); (M.S.)
| | - Michael Stürzl
- Division of Molecular and Experimental Surgery, University Medical Center Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Schwabachanlage 12, 91054 Erlangen, Germany; (E.N.); (M.S.)
| | - Stefania Martini
- IRCCS Ospedale Policlinico San Martino, Immunology Unit, Largo R. Benzi 10, 16132 Genoa, Italy; (S.M.); (M.C.M.)
| | - Maria Cristina Mingari
- IRCCS Ospedale Policlinico San Martino, Immunology Unit, Largo R. Benzi 10, 16132 Genoa, Italy; (S.M.); (M.C.M.)
- Department of Experimental Medicine and Centre of Excellence for Biomedical Research, University of Genoa, Via L.B. Alberti 2, 16132 Genoa, Italy
| | - Gilberto Filaci
- IRCCS Ospedale Policlinico San Martino, Biotherapies Unit, Largo R. Benzi 10, 16132 Genoa, Italy; (G.C.); (G.F.)
- Centre of Excellence for Biomedical Research and Department of Internal Medicine, University of Genoa, Via De Toni 14, 16132 Genoa, Italy
| | - Silvano Ferrini
- IRCCS Ospedale Policlinico San Martino, Biotherapies Unit, Largo R. Benzi 10, 16132 Genoa, Italy; (G.C.); (G.F.)
| | - Marina Fabbi
- IRCCS Ospedale Policlinico San Martino, Biotherapies Unit, Largo R. Benzi 10, 16132 Genoa, Italy; (G.C.); (G.F.)
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50
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Zhang Y, Song J, Zhao Z, Yang M, Chen M, Liu C, Ji J, Zhu D. Single-cell transcriptome analysis reveals tumor immune microenvironment heterogenicity and granulocytes enrichment in colorectal cancer liver metastases. Cancer Lett 2020; 470:84-94. [DOI: 10.1016/j.canlet.2019.10.016] [Citation(s) in RCA: 127] [Impact Index Per Article: 25.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 10/06/2019] [Accepted: 10/08/2019] [Indexed: 02/09/2023]
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