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1
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Joo H, Olea XD, Zhuang A, Zheng B, Kim H, Ronai ZA. Epigenetic mechanisms in melanoma development and progression. Trends Cancer 2025:S2405-8033(25)00099-8. [PMID: 40328568 DOI: 10.1016/j.trecan.2025.04.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2025] [Revised: 04/08/2025] [Accepted: 04/08/2025] [Indexed: 05/08/2025]
Abstract
Knowledge of cancer development and progression gained over the last few decades has enabled mapping of genetic and epigenetic changes unique to different phases of tumor evolution. Here we focus on epigenetic changes that drive melanoma development and progression. We highlight the importance of epigenetic mechanisms which encompass crosstalk with melanoma microenvironment that affect metastasis and therapy resistance. This review summarizes recent advances and describes potential strategies to leverage this knowledge to devise new therapies.
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Affiliation(s)
- Hyunjeong Joo
- Jim and Eleanor Randall Department of Surgery, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Ximena Diaz Olea
- Jim and Eleanor Randall Department of Surgery, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Aojia Zhuang
- Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Bin Zheng
- Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Hyungsoo Kim
- Jim and Eleanor Randall Department of Surgery, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Ze'ev A Ronai
- Jim and Eleanor Randall Department of Surgery, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; Translational Research Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA.
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Feng Y, Liu G, Li H, Cheng L. The landscape of cell lineage tracing. SCIENCE CHINA. LIFE SCIENCES 2025:10.1007/s11427-024-2751-6. [PMID: 40035969 DOI: 10.1007/s11427-024-2751-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Accepted: 09/30/2024] [Indexed: 03/06/2025]
Abstract
Cell fate changes play a crucial role in the processes of natural development, disease progression, and the efficacy of therapeutic interventions. The definition of the various types of cell fate changes, including cell expansion, differentiation, transdifferentiation, dedifferentiation, reprogramming, and state transitions, represents a complex and evolving field of research known as cell lineage tracing. This review will systematically introduce the research history and progress in this field, which can be broadly divided into two parts: prospective tracing and retrospective tracing. The initial section encompasses an array of methodologies pertaining to isotope labeling, transient fluorescent tracers, non-fluorescent transient tracers, non-fluorescent genetic markers, fluorescent protein, genetic marker delivery, genetic recombination, exogenous DNA barcodes, CRISPR-Cas9 mediated DNA barcodes, and base editor-mediated DNA barcodes. The second part of the review covers genetic mosaicism, genomic DNA alteration, TCR/BCR, DNA methylation, and mitochondrial DNA mutation. In the final section, we will address the principal challenges and prospective avenues of enquiry in the field of cell lineage tracing, with a particular focus on the sequencing techniques and mathematical models pertinent to single-cell genetic lineage tracing, and the value of pursuing a more comprehensive investigation at both the spatial and temporal levels in the study of cell lineage tracing.
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Affiliation(s)
- Ye Feng
- Shanghai YangZhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), Tongji University School of Medicine, Shanghai, 201619, China.
| | - Guang Liu
- Department of Vascular Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200023, China.
| | - Haiqing Li
- Department of Cardiac Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| | - Lin Cheng
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
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3
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Gu J, Lv YF, Xia JY, Bai FH, Gong J, Pan GQ, Liu B, Huang L, Guo QN, Hao XL. TC2N maintains stem cell-like characteristics to accelerate lung carcinogenesis by blockade of dual specificity protein phosphatase 3. Cell Biosci 2025; 15:8. [PMID: 39849581 PMCID: PMC11758731 DOI: 10.1186/s13578-025-01348-3] [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: 08/22/2024] [Accepted: 01/10/2025] [Indexed: 01/25/2025] Open
Abstract
BACKGROUND Tandem C2 domains, nuclear (TC2N) is a protein that has been characterized to contain C2A domain, C2B domain, and a short C-terminus with a WHXL motif. In previous studies, we have uncovered the oncogenic role and mechanisms of TC2N in lung cancer: TC2N achieves this by inhibiting the p53 signaling pathway and activating the NF-kappaB signaling pathway. Beyond that, its precise function in tumorigenesis is not fully understood. METHODS TC2N-engineered mice model was used to assess the effect of TC2N knockout on normal lung and urethane-induced carcinogenesis. Tumor tissues of 395 lung cancer patients were subjected to tissue microarray and further assessed the associations of TC2N expression with tumor differentiation degree. The protein levels of TC2N and stem cell markers in cell lines and tissue specimens were monitored by WB and immunohistochemistry. In vitro cell assays were performed to assess the effect of TC2N ectopic expression on the stem cell-like characteristics of lung cancer cells. The downstream signaling pathway or target molecule of TC2N was mined using a combination of transcriptomics and proteomics, and the underlying mechanism was explored by WB and co-IP assays. RESULTS Herein, TC2N appeared to have a strong effect in promoting lung tumorigenesis caused by urethane, whereas it seemed to lose its function in the normal lung. Meanwhile, we found that the functional differences of TC2N between lung tumor and normal lung were linked to its potential role in cancer cell stemness. Function-wise, TC2N overexpression maintained stem-like properties of lung cancer cell. Mechanism-wise, TC2N upregulated the phosphorylation of EGFR, ERK, STAT3 and FAK1 to activate these signaling pathways by the inhibition of DUSP3 phosphatase via a dual mechanism. Firstly, TC2N competes with EGFR, ERK, STAT3 and FAK1 for binding to DUSP3. This competition prevents these signaling molecules from being dephosphorylated by DUSP3, resulting in their sustained activation. Secondly, TC2N bind to DUSP3 and restrict the enzyme's ability to dephosphorylate the signaling molecules. CONCLUSIONS Overall, this study revealed a previously unknown role and mechanism of TC2N in the regulation of tumorigenesis and stemness in lung cancer cells.
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Affiliation(s)
- Jing Gu
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, PR China
| | - Yang-Fan Lv
- Department of Pathology, Xinqiao Hospital, Third Military Medical University, 183 Xinqiao Street, Shapingba District, Chongqing, 400037, PR China
| | - Ji-Ying Xia
- Department of Pathology, Xinqiao Hospital, Third Military Medical University, 183 Xinqiao Street, Shapingba District, Chongqing, 400037, PR China
| | - Fu-Hai Bai
- Department of Anesthesiology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, PR China
| | - Ji Gong
- Department of Pathology, Xinqiao Hospital, Third Military Medical University, 183 Xinqiao Street, Shapingba District, Chongqing, 400037, PR China
| | - Guang-Qiang Pan
- Department of Pathology, Xinqiao Hospital, Third Military Medical University, 183 Xinqiao Street, Shapingba District, Chongqing, 400037, PR China
| | - Bo Liu
- Department of Pathology, Xinqiao Hospital, Third Military Medical University, 183 Xinqiao Street, Shapingba District, Chongqing, 400037, PR China
| | - Lu Huang
- Department of Pathology, Xinqiao Hospital, Third Military Medical University, 183 Xinqiao Street, Shapingba District, Chongqing, 400037, PR China
| | - Qiao-Nan Guo
- Department of Pathology, Xinqiao Hospital, Third Military Medical University, 183 Xinqiao Street, Shapingba District, Chongqing, 400037, PR China.
| | - Xiang-Lin Hao
- Department of Pathology, Xinqiao Hospital, Third Military Medical University, 183 Xinqiao Street, Shapingba District, Chongqing, 400037, PR China.
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4
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Fang F, Wu T, Wang M, Li W, You Z, Chen M, Guan H. Matrix Metalloproteinase-9 is associated with tumor microenvironment remodeling of bladder cancer. Biol Direct 2025; 20:8. [PMID: 39819701 PMCID: PMC11737229 DOI: 10.1186/s13062-025-00599-x] [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: 09/24/2024] [Accepted: 01/07/2025] [Indexed: 01/19/2025] Open
Abstract
Tumor microenvironment (TME) takes an essential part in the bladder cancer progression, which is associated with intercellular cross-talk between stroma cells and cancer. We aimed use bioinformatics tools to analyze tumor microenvironment remodeling in bladder cancer. CIBERSORT and ESTIMATE are bioinformatics tools based on deconvolution for calculating proportions of tumor-infiltrating immune cells and stromal components in TME. We utilized these two algorithms to analyze the immune components of 433 bladder cancer cases from The Cancer Genome Atlas database, aiming to compensate for the current lack of large-sample single-cell information. Then we used Cox regression to analyze the prognostic value of differentially expressed genes, and the protein-protein interaction network was constructed. Matrix Metalloproteinase-9 (MMP9) was identified as a predictive biomarker related to immune microenvironment. Using Gene Set Enrichment Analysis, the genes from the group with high MMP9 expression gathered in items related to immune diseases, and genes in the group with low MMP9 expression were negatively associated with valine, leucine and isoleucine degradation and glycosylphosphatidylinositol anchor biosynthesis. MMP9 expression and presence of macrophages M0 were positively correlated, while naïve B cells, activated dendritic cells, monocytes and plasma cells were negatively correlated. The results were confirmed by brightfield and multiplex fluorescence immunohistochemistry using stained bladder cancer and normal tissue.
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Affiliation(s)
- Fang Fang
- Department of Immunology, School of Laboratory Medicine, Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical University, Bengbu, China
| | - Tiange Wu
- Medical School of Southeast University, Nanjing, China
| | - Mengxue Wang
- Medical School of Southeast University, Nanjing, China
| | - Wenchao Li
- Department of Urology, Affiliated Zhongda Hospital of Southeast University, Nanjing, 210009, China.
| | - Zonghao You
- Department of Urology, Affiliated Zhongda Hospital of Southeast University, Nanjing, 210009, China.
| | - Ming Chen
- Department of Urology, Affiliated Zhongda Hospital of Southeast University, Nanjing, 210009, China.
| | - Han Guan
- Department of Urology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, 233030, China.
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Zheng ZY, Lin W, Su JW, Huang QF, Zhang C, Pan WX, Li EM, Zhang HF, Xu LY. NIR-715 photodynamic therapy induces immunogenic cancer cell death by enhancing the endoplasmic reticulum stress response. Cell Death Dis 2024; 15:890. [PMID: 39695072 DOI: 10.1038/s41419-024-07283-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 11/23/2024] [Accepted: 12/03/2024] [Indexed: 12/20/2024]
Abstract
Effectively interfering with endoplasmic reticulum (ER) function in tumor cells and simultaneously activating an anti-tumor immune microenvironment to attack the tumor cells are promising strategies for cancer treatment. However, precise ER-stress induction is still a huge challenge. In this study, we synthesized a near-infrared (NIR) probe, NIR-715, which induces tumor cell death and inhibits tumor growth without causing apparent side effects. NIR-715 triggers severe ER stress and immunogenic cell death (ICD) after visible light exposure. NIR-715 induced ICD-associated HMGB1 release in vitro and anti-tumor immune responses, including increased cytotoxic T lymphocyte (GZMB+ CD8+ T cell) infiltration and decreased numbers of exhausted T lymphocytes (PD-L1+ CD8+ T cell). These findings suggest that NIR-715 may be a novel agent for "cold" tumor photodynamic therapy (PDT). Schematic illustration of NIR-715 photodynamic therapy for visible light-triggered, endoplasmic reticulum-targeting antitumor therapy.
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Affiliation(s)
- Zhen-Yuan Zheng
- Department of Oncobiology, Department of Basic Medical Sciences, Shantou University Medical College, Shantou, Guangdong, PR China
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Cancer Research Center, Shantou University Medical College, Shantou, 515041, Guangdong, P. R. China
- Chaoshan Branch of State Key Laboratory for Esophageal Cancer Prevention and Treatment, Shantou, China
| | - Wan Lin
- Department of Oncobiology, Department of Basic Medical Sciences, Shantou University Medical College, Shantou, Guangdong, PR China
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Cancer Research Center, Shantou University Medical College, Shantou, 515041, Guangdong, P. R. China
| | - Jia-Wan Su
- Department of Chemistry and Key Laboratory for Preparation and Application of Ordered Structural Materials of Guangdong Province, Shantou University, Science Building, 243 Daxue Road, Shantou, 515063, Guangdong, PR China
| | - Qing-Feng Huang
- Department of Oncobiology, Department of Basic Medical Sciences, Shantou University Medical College, Shantou, Guangdong, PR China
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Cancer Research Center, Shantou University Medical College, Shantou, 515041, Guangdong, P. R. China
| | - Cong Zhang
- Department of Oncobiology, Department of Basic Medical Sciences, Shantou University Medical College, Shantou, Guangdong, PR China
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Cancer Research Center, Shantou University Medical College, Shantou, 515041, Guangdong, P. R. China
| | - Wen-Xing Pan
- Department of Oncobiology, Department of Basic Medical Sciences, Shantou University Medical College, Shantou, Guangdong, PR China
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Cancer Research Center, Shantou University Medical College, Shantou, 515041, Guangdong, P. R. China
| | - En-Min Li
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, 515041, Guangdong, China
| | - He-Feng Zhang
- Department of Chemistry and Key Laboratory for Preparation and Application of Ordered Structural Materials of Guangdong Province, Shantou University, Science Building, 243 Daxue Road, Shantou, 515063, Guangdong, PR China.
| | - Li-Yan Xu
- Department of Oncobiology, Department of Basic Medical Sciences, Shantou University Medical College, Shantou, Guangdong, PR China.
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Cancer Research Center, Shantou University Medical College, Shantou, 515041, Guangdong, P. R. China.
- Chaoshan Branch of State Key Laboratory for Esophageal Cancer Prevention and Treatment, Shantou, China.
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Cheng Y, Zhong W, Chen Y, Tan BSN, Zhao Y, Guo J, Ma M, Zhao Y. Bimetal-Biligand Frameworks for Spatiotemporal Nitric Oxide-Enhanced Sono-Immunotherapy. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2408242. [PMID: 39225414 DOI: 10.1002/adma.202408242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 08/19/2024] [Indexed: 09/04/2024]
Abstract
Sonodynamic therapy can trigger immunogenic cell death to augment immunotherapy, benefiting from its superior spatiotemporal selectivity and non-invasiveness. However, the practical applications of sonosensitizers are hindered by their low efficacy in killing cancer cells and activating immune responses. Here, two US Food and Drug Administration-approved drug ligands (ferricyanide and nitroprusside) and two types of metals (copper/iron) are selected to construct a bimetal-biligand framework (Cu[PBA-NO]). Through elaborate regulation of multiple metal/ligand coordination, the systemically administered Cu[PBA-NO] nanoagent shows sono-catalytic and NO release ability under ultrasound irradiation, which can be used for effective sono-immunotherapy. Moreover, Cu[PBA-NO] can downregulate intracellular glutathione levels that would destroy intracellular redox homeostasis and facilitate reactive oxygen species accumulation. The released tumor-associated antigens subsequently facilitate dendritic cell maturation within the tumor-draining lymph node, effectively initiating a T cell-mediated immune response and thereby bolstering the capacity to identify and combat cancer cells. This study paves a new avenue for the efficient cancer sono-immunotherapy.
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Affiliation(s)
- Yu Cheng
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore, 637371, Singapore
| | - Wenbin Zhong
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore, 637371, Singapore
| | - Yun Chen
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore, 637371, Singapore
| | - Brynne Shu Ni Tan
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore, 637371, Singapore
| | - Yue Zhao
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore, 637371, Singapore
| | - Jingjing Guo
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore, 637371, Singapore
| | - Mengmeng Ma
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore, 637371, Singapore
| | - Yanli Zhao
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore, 637371, Singapore
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7
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Bridges K, Pizzurro GA, Baysoy A, Baskaran JP, Xu Z, Mathew V, Tripple V, LaPorte M, Park K, Damsky W, Kluger H, Fan R, Kaech SM, Bosenberg MW, Miller-Jensen K. Mapping intratumoral myeloid-T cell interactomes at single-cell resolution reveals targets for overcoming checkpoint inhibitor resistance. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.28.620093. [PMID: 39554094 PMCID: PMC11565996 DOI: 10.1101/2024.10.28.620093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/19/2024]
Abstract
Effective cancer immunotherapies restore anti-tumor immunity by rewiring cell-cell communication. Treatment-induced changes in communication can be inferred from single-cell RNA-sequencing (scRNA-seq) data, but current methods do not effectively manage heterogeneity within cell types. Here we developed a computational approach to efficiently analyze scRNA-seq-derived, single-cell-resolved cell-cell interactomes, which we applied to determine how agonistic CD40 (CD40ag) alters immune cell crosstalk alone, across tumor models, and in combination with immune checkpoint blockade (ICB). Our analyses suggested that CD40ag improves responses to ICB by targeting both immuno-stimulatory and immunosuppressive macrophage subsets communicating with T cells, and we experimentally validated a spatial basis for these subsets with immunofluorescence and spatial transcriptomics. Moreover, treatment with CD40ag and ICB established coordinated myeloid-T cell interaction hubs that are critical for reestablishing antitumor immunity. Our work advances the biological significance of hypotheses generated from scRNA-seq-derived cell-cell interactomes and supports the clinical translation of myeloid-targeted therapies for ICB-resistant tumors.
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Affiliation(s)
- Kate Bridges
- Department of Biomedical Engineering, Yale University, New Haven, CT 06511, USA
- Present address: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | | | - Alev Baysoy
- Department of Biomedical Engineering, Yale University, New Haven, CT 06511, USA
| | - Janani P. Baskaran
- Department of Biomedical Engineering, Yale University, New Haven, CT 06511, USA
| | - Ziyan Xu
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
- School of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA
| | - Varsha Mathew
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Victoria Tripple
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Michael LaPorte
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Koonam Park
- Department of Dermatology, Yale School of Medicine, New Haven, CT 06520, USA
| | - William Damsky
- Department of Dermatology, Yale School of Medicine, New Haven, CT 06520, USA
- Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA
| | - Harriet Kluger
- Department of Medicine (Medical Oncology), Yale School of Medicine, New Haven, CT 06520, USA
- Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520, USA
- Yale Cancer Center, Yale School of Medicine, New Haven, CT 06520, USA
| | - Rong Fan
- Department of Biomedical Engineering, Yale University, New Haven, CT 06511, USA
- Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA
- Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520, USA
- Yale Cancer Center, Yale School of Medicine, New Haven, CT 06520, USA
| | - Susan M. Kaech
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Marcus W. Bosenberg
- Department of Dermatology, Yale School of Medicine, New Haven, CT 06520, USA
- Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA
- Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520, USA
- Yale Cancer Center, Yale School of Medicine, New Haven, CT 06520, USA
- Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA
| | - Kathryn Miller-Jensen
- Department of Biomedical Engineering, Yale University, New Haven, CT 06511, USA
- Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06511, USA
- Systems Biology Institute, Yale University, New Haven, CT 06511, USA
- Lead contact
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Montazeri Aliabadi H. Molecular Targets for Breast Cancer Therapy. Biomolecules 2024; 14:1219. [PMID: 39456152 PMCID: PMC11506731 DOI: 10.3390/biom14101219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Accepted: 09/25/2024] [Indexed: 10/28/2024] Open
Abstract
Breast cancer is by far the most common cancer in women, and for a while, it surpassed lung cancer as the most diagnosed cancer, regardless of gender, in 2020 [...].
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Affiliation(s)
- Hamidreza Montazeri Aliabadi
- Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, Irvine, CA 92618, USA
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9
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Iavarone M, Nault JC, Cabibbo G, Torres F, Reig M. Indolent cancer and pattern of progression: Two missing parameters in trial design for hepatology. Hepatology 2024; 79:1452-1462. [PMID: 37399245 PMCID: PMC11095876 DOI: 10.1097/hep.0000000000000527] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 01/20/2023] [Indexed: 07/05/2023]
Abstract
The indolent and aggressive behaviors of HCC might have a role in clinical trial (CT) results; however, the indolent HCC is less analyzed compared to others cancer. Indolent profile could be characterized as follows: (1) patients with low risk of progression itself due to the HCC molecular profile and/or due to the interaction between cancer cell their microenvironment; (2) patients who achieve objective response or present spontaneous regression; and (3) patients who develop radiological progression with no consequence on either the liver function or general status, and without trigger a change in the tumor stage. Patients with "indolent HCC" generally never develop cancer-related symptoms neither die for HCC-related causes. Thus, we hypothesize that the imbalance in the proportion of "indolent" versus "aggressive HCC" between arms or the underestimation/overestimation of HCC behavior at baseline in single-arm CT could be associated with CT failure or under-overestimation of trial results. The "indolent progression" may also explain the discrepancy between radiological progression-based end points and survival. Moreover, we discuss the related causes that explain the indolent profile of HCC and propose (1) refining the progression-related end point by the pattern of progression to minimize the limitations of the current end points; (2) considering alternative statistical tools for survival analysis such as milestone survival, or restricted mean survival time to capture the value of indolent HCC. According to these considerations, we propose incorporating novel end points into the single arm of phase I/II CT as exploratory analysis or as a secondary end point in phase III CT.
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Affiliation(s)
- Massimo Iavarone
- Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico—Division of Gastroenterology and Hepatology, Milan, Italy
| | - Jean-Charles Nault
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris Cité, team « Functional Genomics of Solid Tumors », Equipe labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, Paris, France
- Service d’hépatologie, Hôpital Avicenne, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bobigny, France
- Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris nord, Bobigny, France
| | - Giuseppe Cabibbo
- Section of Gastroenterology & Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, Palermo, Italy
| | - Ferran Torres
- Biostatistics Unit, Medical School, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Maria Reig
- Liver Oncology Unit. Liver Unit, Hospital Clínic Barcelona, Barcelona, Spain
- BCLC group, FUNDACIO/IDIBAPS, Barcelona, Spain
- CIBEREHD, Madrid, Spain
- Universitat de Barcelona, Barcelona, Spain
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10
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Yan Z, Liu Z, Zhang H, Guan X, Xu H, Zhang J, Zhao Q, Wang S. Current trends in gas-synergized phototherapy for improved antitumor theranostics. Acta Biomater 2024; 174:1-25. [PMID: 38092250 DOI: 10.1016/j.actbio.2023.12.012] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 11/14/2023] [Accepted: 12/06/2023] [Indexed: 12/21/2023]
Abstract
Phototherapy, such as photothermal therapy (PTT) and photodynamic therapy (PDT), has been considered an elegant solution to eradicate tumors due to its minimal invasiveness and low systemic toxicity. Nevertheless, it is still challenging for phototherapy to achieve ideal outcomes and clinical translation due to its inherent drawbacks. Owing to the unique biological functions, diverse gases have attracted growing attention in combining with phototherapy to achieve super-additive therapeutic effects. Specifically, gases such as nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S) have been proven to kill tumor cells by inducing mitochondrial damage in synergy with phototherapy. Additionally, several gases not only enhance the thermal damage in PTT and the reactive oxygen species (ROS) production in PDT but also improve the tumor accumulation of photoactive agents. The inflammatory responses triggered by hyperthermia in PTT are also suppressed by the combination of gases. Herein, we comprehensively review the latest studies on gas-synergized phototherapy for cancer therapy, including (1) synergistic mechanisms of combining gases with phototherapy; (2) design of nanoplatforms for gas-synergized phototherapy; (3) multimodal therapy based on gas-synergized phototherapy; (4) imaging-guided gas-synergized phototherapy. Finally, the current challenges and future opportunities of gas-synergized phototherapy for tumor treatment are discussed. STATEMENT OF SIGNIFICANCE: 1. The novelty and significance of the work with respect to the existing literature. (1) Strategies to design nanoplatforms for gas-synergized anti-tumor phototherapy have been summarized for the first time. Meanwhile, the integration of various imaging technologies and therapy modalities which endow these nanoplatforms with advanced theranostic capabilities has been summarized. (2) The mechanisms by which gases synergize with phototherapy to eradicate tumors are innovatively and comprehensively summarized. 2. The scientific impact and interest. This review elaborates current trends in gas-synergized anti-tumor phototherapy, with special emphases on synergistic anti-tumor mechanisms and rational design of therapeutic nanoplatforms to achieve this synergistic therapy. It aims to provide valuable guidance for researchers in this field.
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Affiliation(s)
- Ziwei Yan
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning Province 110016, PR China
| | - Zhu Liu
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning Province 110016, PR China
| | - Haotian Zhang
- Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning Province 110016, PR China
| | - Xinyao Guan
- Experimental Teaching Center, Faculty of Functional Food and Wine, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning Province 110016, PR China
| | - Hongwei Xu
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning Province 110016, PR China
| | - Jinghai Zhang
- Department of Biomedical Engineering, School of Medical Devices, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning Province 110016, PR China
| | - Qinfu Zhao
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning Province 110016, PR China.
| | - Siling Wang
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning Province 110016, PR China.
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11
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Olejarz W, Basak G. Emerging Therapeutic Targets and Drug Resistance Mechanisms in Immunotherapy of Hematological Malignancies. Cancers (Basel) 2023; 15:5765. [PMID: 38136311 PMCID: PMC10741639 DOI: 10.3390/cancers15245765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 11/22/2023] [Accepted: 12/06/2023] [Indexed: 12/24/2023] Open
Abstract
CAR-T cell therapy has revolutionized the treatment of hematological malignancies with high remission rates in the case of ALL and NHL. This therapy has some limitations such as long manufacturing periods, persistent restricted cell sources and high costs. Moreover, combination regimens increase the risk of immune-related adverse events, so the identification new therapeutic targets is important to minimize the risk of toxicities and to guide more effective approaches. Cancer cells employ several mechanisms to evade immunosurveillance, which causes resistance to immunotherapy; therefore, a very important therapeutic approach is to focus on the development of rational combinations of targeted therapies with non-overlapping toxicities. Recent progress in the development of new inhibitory clusters of differentiation (CDs), signaling pathway molecules, checkpoint inhibitors, and immunosuppressive cell subsets and factors in the tumor microenvironment (TME) has significantly improved anticancer responses. Novel strategies regarding combination immunotherapies with CAR-T cells are the most promising approach to cure cancer.
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Affiliation(s)
- Wioletta Olejarz
- Department of Biochemistry and Pharmacogenomics, Faculty of Pharmacy, Medical University of Warsaw, 02-091 Warsaw, Poland
- Centre for Preclinical Research, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Grzegorz Basak
- Department of Hematology, Transplantation and Internal Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland;
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12
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Hodara E, Mades A, Swartz L, Iqbal M, Xu T, Bsteh D, Farnham P, Rhie S, Goldkorn A. m 6A epitranscriptome analysis reveals differentially methylated transcripts that drive early chemoresistance in bladder cancer. NAR Cancer 2023; 5:zcad054. [PMID: 38023731 PMCID: PMC10653028 DOI: 10.1093/narcan/zcad054] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 10/24/2023] [Accepted: 11/07/2023] [Indexed: 12/01/2023] Open
Abstract
N 6-Methyladenosine (m6A) RNA modifications dynamically regulate messenger RNA processing, differentiation and cell fate. Given these functions, we hypothesized that m6A modifications play a role in the transition to chemoresistance. To test this, we took an agnostic discovery approach anchored directly to chemoresistance rather than to any particular m6A effector protein. Specifically, we used methyl-RNA immunoprecipitation followed by sequencing (MeRIP-seq) in parallel with RNA sequencing to identify gene transcripts that were both differentially methylated and differentially expressed between cisplatin-sensitive and cisplatin-resistant bladder cancer (BC) cells. We filtered and prioritized these genes using clinical and functional database tools, and then validated several of the top candidates via targeted quantitative polymerase chain reaction (qPCR) and MeRIP-PCR. In cisplatin-resistant cells, SLC7A11 transcripts had decreased methylation associated with decreased m6A reader YTHDF3 binding, prolonged RNA stability, and increased RNA and protein levels, leading to reduced ferroptosis and increased survival. Consistent with this, cisplatin-sensitive BC cell lines and patient-derived organoids exposed to cisplatin for as little as 48 h exhibited similar mechanisms of SLC7A11 upregulation and chemoresistance, trends that were also reflected in public cancer survival databases. Collectively, these findings highlight epitranscriptomic plasticity as a mechanism of rapid chemoresistance and a potential therapeutic target.
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Affiliation(s)
- Emmanuelle Hodara
- Division of Medical Oncology, Department of Medicine, Keck School of Medicine of USC and Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA
| | - Aubree Mades
- Division of Medical Oncology, Department of Medicine, Keck School of Medicine of USC and Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA
| | - Lisa Swartz
- Division of Medical Oncology, Department of Medicine, Keck School of Medicine of USC and Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA
| | - Maheen Iqbal
- Division of Medical Oncology, Department of Medicine, Keck School of Medicine of USC and Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA
| | - Tong Xu
- Division of Medical Oncology, Department of Medicine, Keck School of Medicine of USC and Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA
| | - Daniel Bsteh
- Division of Medical Oncology, Department of Medicine, Keck School of Medicine of USC and Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA
| | - Peggy J Farnham
- Department of Biochemistry and Molecular Medicine, Keck School of Medicine of USC, Los Angeles, CA 90033, USA
| | - Suhn K Rhie
- Department of Biochemistry and Molecular Medicine, Keck School of Medicine of USC, Los Angeles, CA 90033, USA
| | - Amir Goldkorn
- Division of Medical Oncology, Department of Medicine, Keck School of Medicine of USC and Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA
- Department of Biochemistry and Molecular Medicine, Keck School of Medicine of USC, Los Angeles, CA 90033, USA
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13
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Alzamami A. Implications of single-cell immune landscape of tumor microenvironment for the colorectal cancer diagnostics and therapy. Med Oncol 2023; 40:352. [PMID: 37950801 DOI: 10.1007/s12032-023-02226-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 10/18/2023] [Indexed: 11/13/2023]
Abstract
Colorectal cancer (CRC) originates from the polyps lining the colon and is among the most common types of cancer. With the increasing popularity of single-cell sequencing technologies, researchers have been able to better understand the immune landscape of colorectal cancer, by analyzing their expression and interactions in detail with the tumor microenvironment (TME) at single-cell level. Since the tumor-immune cell interactions play a critical part in the advancement as well as treatment response in colorectal cancer, the release of inhibitory factors such as T cells are important for recognizing and destroying cancer cells. Such information is vital to identify immunotherapeutic targets for cure and monitoring response to treatments. Therefore, a comprehensive single-cell studies-based overview of key immunogenic agents regulating the TME of CRC is provided in this review. Tumor-associated macrophages can promote tumor growth and resistance to treatment by releasing factors that inhibit the function of other immune cells. Additionally, colorectal cancer cells can express programmed cell death protein 1 and its ligand, which can also inhibit T-cell function. Researchers have found that certain types of immune cells, prominently T cells, natural killer, and dendritic cells, can have a positive impact on the prognosis of colorectal cancer patients. Treatments like immune checkpoint inhibitors and CAR-T therapies that help to release the inhibitory signals from the cancer cells allow the immune cells to function more effectively.
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Affiliation(s)
- Ahmad Alzamami
- Clinical Laboratory Science Department, College of Applied Medical Sciences, Shaqra University, 11961, Al-Quwayiyah, Saudi Arabia.
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14
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Giordano G, Ferioli E, Guareschi D, Tafuni A. Dedifferentiated Endometrial Carcinoma: A Rare Aggressive Neoplasm-Clinical, Morphological and Immunohistochemical Features. Cancers (Basel) 2023; 15:5155. [PMID: 37958329 PMCID: PMC10647464 DOI: 10.3390/cancers15215155] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 10/22/2023] [Accepted: 10/24/2023] [Indexed: 11/15/2023] Open
Abstract
Dedifferentiated endometrioid adenocarcinoma is characterised by the coexistence of an undifferentiated carcinoma and a low-grade endometrioid adenocarcinoma. The low-grade component in this subtype of endometrial carcinoma is Grade 1 or 2 according to the Federation of Gynaecology and Obstetrics (FIGO) grading system. The coexistence of low-grade endometrial carcinoma and solid undifferentiated carcinoma can cause diagnostic problems on histological examination. In fact, this combination can often be mistaken for a more common Grade 2 or Grade 3 endometrial carcinoma. Therefore, this subtype of uterine carcinoma can often go under-recognised. An accurate diagnosis of dedifferentiated endometrial carcinoma is mandatory because of its poorer prognosis compared to Grade 3 endometrial carcinoma, with a solid undifferentiated component that can amount to as much as 20% of the entire tumour. The aim of this review is to provide clinical, immunohistochemical, and molecular data to aid with making an accurate histological diagnosis and to establish whether there are any findings which could have an impact on the prognosis or therapeutic implications of this rare and aggressive uterine neoplasm.
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Affiliation(s)
- Giovanna Giordano
- Department of Medicine and Surgery, Pathology Unit, University of Parma, Viale A. Gramsci, 14, 43126 Parma, Italy; (E.F.); (A.T.)
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15
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Rani B, Ignatz-Hoover JJ, Rana PS, Driscoll JJ. Current and Emerging Strategies to Treat Urothelial Carcinoma. Cancers (Basel) 2023; 15:4886. [PMID: 37835580 PMCID: PMC10571746 DOI: 10.3390/cancers15194886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Revised: 09/25/2023] [Accepted: 09/25/2023] [Indexed: 10/15/2023] Open
Abstract
Urothelial cell carcinoma (UCC, bladder cancer, BC) remains a difficult-to-treat malignancy with a rising incidence worldwide. In the U.S., UCC is the sixth most incident neoplasm and ~90% of diagnoses are made in those >55 years of age; it is ~four times more commonly observed in men than women. The most important risk factor for developing BC is tobacco smoking, which accounts for ~50% of cases, followed by occupational exposure to aromatic amines and ionizing radiation. The standard of care for advanced UCC includes platinum-based chemotherapy and programmed cell death (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors, administered as frontline, second-line, or maintenance therapy. UCC remains generally incurable and is associated with intrinsic and acquired drug and immune resistance. UCC is lethal in the metastatic state and characterized by genomic instability, high PD-L1 expression, DNA damage-response mutations, and a high tumor mutational burden. Although immune checkpoint inhibitors (ICIs) achieve long-term durable responses in other cancers, their ability to achieve similar results with metastatic UCC (mUCC) is not as well-defined. Here, we discuss therapies to improve UCC management and how comprehensive tumor profiling can identify actionable biomarkers and eventually fulfill the promise of precision medicine for UCC patients.
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Affiliation(s)
- Berkha Rani
- Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; (B.R.); (J.J.I.-H.); (P.S.R.)
| | - James J. Ignatz-Hoover
- Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; (B.R.); (J.J.I.-H.); (P.S.R.)
- Division of Hematology & Oncology, Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
- Adult Hematologic Malignancies & Stem Cell Transplant Section, Seidman Cancer Center, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA
| | - Priyanka S. Rana
- Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; (B.R.); (J.J.I.-H.); (P.S.R.)
- Division of Hematology & Oncology, Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
- Adult Hematologic Malignancies & Stem Cell Transplant Section, Seidman Cancer Center, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA
| | - James J. Driscoll
- Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; (B.R.); (J.J.I.-H.); (P.S.R.)
- Division of Hematology & Oncology, Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
- Adult Hematologic Malignancies & Stem Cell Transplant Section, Seidman Cancer Center, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA
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16
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Somu P, Basavegowda N, Gomez LA, Jayaprakash HV, Puneetha GK, Yadav AK, Paul S, Baek KH. Crossroad between the Heat Shock Protein and Inflammation Pathway in Acquiring Drug Resistance: A Possible Target for Future Cancer Therapeutics. Biomedicines 2023; 11:2639. [PMID: 37893013 PMCID: PMC10604354 DOI: 10.3390/biomedicines11102639] [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: 08/31/2023] [Revised: 09/23/2023] [Accepted: 09/25/2023] [Indexed: 10/29/2023] Open
Abstract
The development of multidrug resistance (MDR) against chemotherapeutic agents has become a major impediment in cancer therapy. Understanding the underlying mechanism behind MDR can guide future treatment for cancer with better therapeutic outcomes. Recent studies evidenced that crossroads interaction between the heat shock proteins (HSP) and inflammatory responses under the tumor microenvironment plays a pivotal role in modulating drug responsiveness and drug resistance through a complex cytological process. This review aims to investigate the interrelationship between inflammation and HSP in acquiring multiple drug resistance and investigate strategies to overcome the drug resistance to improve the efficacy of cancer treatment. HSP plays a dual regulatory effect as an immunosuppressive and immunostimulatory agent, involving the simultaneous blockade of multiple signaling pathways in acquiring MDR. For example, HSP27 shows biological effects on monocytes by causing IL10 and TNFα secretion and blocking monocyte differentiation to normal dendritic cells and tumor-associated macrophages to promote cancer progression and chemoresistance. Thus, the HSP function and immune-checkpoint release modalities provide a therapeutic target for a therapeutically beneficial approach for enhancing anti-tumor immune responses. The interconnection between inflammation and HSP, along with the tumor microenvironment in acquiring drug resistance, has become crucial for rationalizing the effect of HSP immunomodulatory activity with immune checkpoint blockade. This relationship can overcome drug resistance and assist in the development of novel combinatorial cancer immunotherapy in fighting cancer with decreasing mortality rates.
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Affiliation(s)
- Prathap Somu
- Department of Biotechnology and Chemical Engineering, School of Civil & Chemical Engineering, Manipal University Jaipur, Dehmi Kalan, Jaipur 303007, India;
| | - Nagaraj Basavegowda
- Department of Biotechnology, Yeungnam University, Gyeongsan 38451, Republic of Korea;
| | - Levin Anbu Gomez
- Department of Biotechnology, School of Agriculture and Bioscience, Karunya Institute of Technology and Sciences (Deemed-to-be University), Karunya Nagar, Coimbatore 641114, India;
| | | | | | - Akhilesh Kumar Yadav
- Department of Environmental Engineering and Management, Chaoyang University of Technology, Taichung 413310, Taiwan;
| | - Subhankar Paul
- Structural Biology and Nanomedicine Laboratory, Department of Biotechnology and Medical Engineering, National Institute of Technology, Rourkela 769008, India
| | - Kwang-Hyun Baek
- Department of Biotechnology, Yeungnam University, Gyeongsan 38451, Republic of Korea;
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17
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Li Z, Zhang X, Jin Q, Zhang Q, Yue Q, Fujimoto M, Jin G. Development of a Macrophage-Related Risk Model for Metastatic Melanoma. Int J Mol Sci 2023; 24:13752. [PMID: 37762054 PMCID: PMC10530689 DOI: 10.3390/ijms241813752] [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: 07/28/2023] [Revised: 08/20/2023] [Accepted: 09/01/2023] [Indexed: 09/29/2023] Open
Abstract
As a metastasis-prone malignancy, the metastatic form and location of melanoma seriously affect its prognosis. Although effective surgical methods and targeted drugs are available to enable the treatment of carcinoma in situ, for metastatic tumors, the diagnosis, prognosis assessment and development of immunotherapy are still pending. This study aims to integrate multiple bioinformatics approaches to identify immune-related molecular targets viable for the treatment and prognostic assessment of metastatic melanoma, thus providing new strategies for its use as an immunotherapy. Immunoinfiltration analysis revealed that M1-type macrophages have significant infiltration differences in melanoma development and metastasis. In total, 349 genes differentially expressed in M1-type macrophages and M2-type macrophages were extracted from the MSigDB database. Then we derived an intersection of these genes and 1111 melanoma metastasis-related genes from the GEO database, and 31 intersected genes identified as melanoma macrophage immunomarkers (MMIMs) were obtained. Based on MMIMs, a risk model was constructed using the Lasso algorithm and regression analysis, which contained 10 genes (NMI, SNTB2, SLC1A4, PDE4B, CLEC2B, IFI27, COL1A2, MAF, LAMP3 and CCDC69). Patients with high+ risk scores calculated via the model have low levels of infiltration by CD8+ T cells and macrophages, which implies a poor prognosis for patients with metastatic cancer. DCA decision and nomogram curves verify the high sensitivity and specificity of this model for metastatic cancer patients. In addition, 28 miRNAs, 90 transcription factors and 29 potential drugs were predicted by targeting the 10 MMIMs derived from this model. Overall, we developed and validated immune-related prognostic models, which accurately reflected the prognostic and immune infiltration characteristics of patients with melanoma metastasis. The 10 MMIMs may also be prospective targets for immunotherapy.
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Affiliation(s)
- Zhaoxiang Li
- Department of Immunology and Pathogenic Biology, Yanbian University Medical College, Yanji 133002, China; (Z.L.); (X.Z.); (Q.J.); (Q.Z.); (Q.Y.)
| | - Xinyuan Zhang
- Department of Immunology and Pathogenic Biology, Yanbian University Medical College, Yanji 133002, China; (Z.L.); (X.Z.); (Q.J.); (Q.Z.); (Q.Y.)
| | - Quanxin Jin
- Department of Immunology and Pathogenic Biology, Yanbian University Medical College, Yanji 133002, China; (Z.L.); (X.Z.); (Q.J.); (Q.Z.); (Q.Y.)
| | - Qi Zhang
- Department of Immunology and Pathogenic Biology, Yanbian University Medical College, Yanji 133002, China; (Z.L.); (X.Z.); (Q.J.); (Q.Z.); (Q.Y.)
| | - Qi Yue
- Department of Immunology and Pathogenic Biology, Yanbian University Medical College, Yanji 133002, China; (Z.L.); (X.Z.); (Q.J.); (Q.Z.); (Q.Y.)
| | - Manabu Fujimoto
- Laboratory of Cutaneous Immunology, Osaka University Immunology Frontier Research Center, Department of Dermatology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan;
| | - Guihua Jin
- Department of Immunology and Pathogenic Biology, Yanbian University Medical College, Yanji 133002, China; (Z.L.); (X.Z.); (Q.J.); (Q.Z.); (Q.Y.)
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18
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Tian H, Li Y, Lin J, Zhu F, Hou Z, Wang P, Liu X. Programmed Nanoreactors Boost Immune Response through ROS Cascade Amplification along with RNS Storm. ACS MATERIALS LETTERS 2023; 5:2542-2555. [DOI: 10.1021/acsmaterialslett.3c00676] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/23/2025]
Affiliation(s)
- Haina Tian
- Key Laboratory of Biomedical Engineering of Fujian Province & Research Center of Biomedical Engineering of Xiamen, Department of Biomaterials, Xiamen University, Xiamen 361005, China
- Key Laboratory of Design and Assembly of Functional Nanostructures, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, P. R. China
- Department of Translational Medicine, Xiamen Institute of Rare Earth Materials, Chinese Academy of Sciences, Xiamen 361021, P. R. China
| | - Yang Li
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, P. R. China
- Key Laboratory of Design and Assembly of Functional Nanostructures, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, P. R. China
- Department of Translational Medicine, Xiamen Institute of Rare Earth Materials, Chinese Academy of Sciences, Xiamen 361021, P. R. China
| | - Jinyan Lin
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, P. R. China
- Key Laboratory of Design and Assembly of Functional Nanostructures, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, P. R. China
- Department of Translational Medicine, Xiamen Institute of Rare Earth Materials, Chinese Academy of Sciences, Xiamen 361021, P. R. China
| | - Fukai Zhu
- Collaborative Innovation Center of Mushroom Health Industry, Minnan Normal University, Zhangzhou, Fujian 363000, P. R. China
| | - Zhenqing Hou
- Key Laboratory of Biomedical Engineering of Fujian Province & Research Center of Biomedical Engineering of Xiamen, Department of Biomaterials, Xiamen University, Xiamen 361005, China
| | - Peiyuan Wang
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, P. R. China
- Key Laboratory of Design and Assembly of Functional Nanostructures, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, P. R. China
- Department of Translational Medicine, Xiamen Institute of Rare Earth Materials, Chinese Academy of Sciences, Xiamen 361021, P. R. China
| | - Xiaolong Liu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, P. R. China
- Key Laboratory of Design and Assembly of Functional Nanostructures, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, P. R. China
- Department of Translational Medicine, Xiamen Institute of Rare Earth Materials, Chinese Academy of Sciences, Xiamen 361021, P. R. China
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19
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Giraulo C, Turiello R, Orlando L, Leonardelli S, Landsberg J, Belvedere R, Rolshoven G, Müller CE, Hölzel M, Morello S. The CD73 is induced by TGF-β1 triggered by nutrient deprivation and highly expressed in dedifferentiated human melanoma. Biomed Pharmacother 2023; 165:115225. [PMID: 37517292 DOI: 10.1016/j.biopha.2023.115225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 07/18/2023] [Accepted: 07/23/2023] [Indexed: 08/01/2023] Open
Abstract
CD73 is the key enzyme in the generation of extracellular adenosine, a mediator involved in tumor progression, tumor immune escape and resistance to anti-cancer therapeutics. Microenvironmental conditions influence the expression of CD73 in tumor cells. However how CD73 expression and activity is regulated in a stress condition of lower nutrient availability are largely unknown. Our results indicate that serum starvation leads to a marked up-regulation of CD73 expression on A375 melanoma cells in a time-dependent manner. The cell-surface expression of CD73 is associated with an increased release of TGF-β1 by starved cells. Blockade of TGF-β1 receptors or TGFβ/SMAD3 signaling pathway significantly reduce the expression of CD73 induced by starvation. Treatment of cells with rTGF-β1 up-regulates the expression of CD73 in a concentration-dependent manner, confirming the role of this pathway in regulating CD73 in melanoma A375 cells. The increased expression of CD73 is associated with enhanced AMPase activity, which is selectively reduced by inhibitors of CD73 activity, APCP and PSB-12489. Pharmacological blockade of CD73 significantly inhibits invasion of melanoma cells in a transwell system. Furthermore, using multiplex immunofluorescence imaging we found that, within human melanoma metastases, tumor cells at the dedifferentiated stage show the highest CD73 protein expression. In summary, our data provide new insights into the mechanism regulating the expression/activity of CD73 in melanoma cells in a condition of lower availability of nutrients, which is a common feature of the tumor microenvironment. Within human metastatic melanoma tissues elevated protein expression of CD73 is associated with an invasive-like phenotype.
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Affiliation(s)
- Caterina Giraulo
- Department of Pharmacy, University of Salerno, Fisciano, SA, Italy
| | - Roberta Turiello
- Institute of Experimental Oncology, University Hospital Bonn (UKB), University of Bonn, Bonn, Germany
| | - Lavinia Orlando
- Department of Pharmacy, University of Salerno, Fisciano, SA, Italy; PhD Program in Drug Discovery and Development, University of Salerno, Fisciano, Italy
| | - Sonia Leonardelli
- Institute of Experimental Oncology, University Hospital Bonn (UKB), University of Bonn, Bonn, Germany
| | - Jennifer Landsberg
- Laboratory of Experimental Dermatology, Department of Dermatology and Allergy, University of Bonn, Bonn, Germany
| | | | - Georg Rolshoven
- PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, Bonn, Germany
| | - Christa E Müller
- PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, Bonn, Germany
| | - Michael Hölzel
- Institute of Experimental Oncology, University Hospital Bonn (UKB), University of Bonn, Bonn, Germany
| | - Silvana Morello
- Department of Pharmacy, University of Salerno, Fisciano, SA, Italy.
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20
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Montazeri Aliabadi H, Manda A, Sidgal R, Chung C. Targeting Breast Cancer: The Familiar, the Emerging, and the Uncharted Territories. Biomolecules 2023; 13:1306. [PMID: 37759706 PMCID: PMC10526846 DOI: 10.3390/biom13091306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 08/16/2023] [Accepted: 08/22/2023] [Indexed: 09/29/2023] Open
Abstract
Breast cancer became the most diagnosed cancer in the world in 2020. Chemotherapy is still the leading clinical strategy in breast cancer treatment, followed by hormone therapy (mostly used in hormone receptor-positive types). However, with our ever-expanding knowledge of signaling pathways in cancer biology, new molecular targets are identified for potential novel molecularly targeted drugs in breast cancer treatment. While this has resulted in the approval of a few molecularly targeted drugs by the FDA (including drugs targeting immune checkpoints), a wide array of signaling pathways seem to be still underexplored. Also, while combinatorial treatments have become common practice in clinics, the majority of these approaches seem to combine molecularly targeted drugs with chemotherapeutic agents. In this manuscript, we start by analyzing the list of FDA-approved molecularly targeted drugs for breast cancer to evaluate where molecular targeting stands in breast cancer treatment today. We will then provide an overview of other options currently under clinical trial or being investigated in pre-clinical studies.
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Affiliation(s)
- Hamidreza Montazeri Aliabadi
- Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, Irvine, CA 92618, USA
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21
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Grolleau E, Candiracci J, Lescuyer G, Barthelemy D, Benzerdjeb N, Haon C, Geiguer F, Raffin M, Hardat N, Balandier J, Rabeuf R, Chalabreysse L, Wozny AS, Rommelaere G, Rodriguez-Lafrasse C, Subtil F, Couraud S, Herzog M, Payen-Gay L. Circulating H3K27 Methylated Nucleosome Plasma Concentration: Synergistic Information with Circulating Tumor DNA Molecular Profiling. Biomolecules 2023; 13:1255. [PMID: 37627320 PMCID: PMC10452235 DOI: 10.3390/biom13081255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 08/04/2023] [Accepted: 08/07/2023] [Indexed: 08/27/2023] Open
Abstract
The molecular profiling of circulating tumor DNA (ctDNA) is a helpful tool not only in cancer treatment, but also in the early detection of relapse. However, the clinical interpretation of a ctDNA negative result remains challenging. The characterization of circulating nucleosomes (carrying cell-free DNA) and associated epigenetic modifications (playing a key role in the tumorigenesis of different cancers) may provide useful information for patient management, by supporting the contributive value of ctDNA molecular profiling. Significantly elevated concentrations of H3K27Me3 nucleosomes were found in plasmas at the diagnosis, and during the follow-up, of NSCLC patients, compared to healthy donors (p-value < 0.0001). By combining the H3K27Me3 level and the ctDNA molecular profile, we found that 25.5% of the patients had H3K27Me3 levels above the cut off, and no somatic alteration was detected at diagnosis. This strongly supports the presence of non-mutated ctDNA in the corresponding plasma. During the patient follow-up, a high H3K27Me3-nucleosome level was found in 15.1% of the sample, despite no somatic mutations being detected, allowing the identification of disease progression from 43.1% to 58.2% over molecular profiling alone. Measuring H3K27Me3-nucleosome levels in combination with ctDNA molecular profiling may improve confidence in the negative molecular result for cfDNA in lung cancer at diagnosis, and may also be a promising biomarker for molecular residual disease (MRD) monitoring, during and/or after treatment.
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Affiliation(s)
- Emmanuel Grolleau
- Center for Innovation in Cancerology of Lyon (CICLY) EA 3738, Faculty of Medicine and Maieutic Lyon Sud, Claude Bernard University Lyon I, 69921 Oullins, France
- Pulmonology Department, Lyon Sud Hospital, Hospices Civils de Lyon, 69495 Pierre-Bénite, France
| | - Julie Candiracci
- Belgian Volition SRL, Parc Scientifique Créalys, 5032 Isnes, Belgium
| | - Gaelle Lescuyer
- Center for Innovation in Cancerology of Lyon (CICLY) EA 3738, Faculty of Medicine and Maieutic Lyon Sud, Claude Bernard University Lyon I, 69921 Oullins, France
- Institute of Pharmaceutical and Biological Sciences (ISPB), Claude Bernard University Lyon I, 69373 Lyon, France
- Department of Biochemistry and Molecular Biology, Lyon-Sud Hospital, Hospices Civils de Lyon, 69495 Pierre-Bénite, France
- Circulating Cancer (CIRCAN) Program, Hospices Civils de Lyon, Cancer Institute, 69495 Pierre-Bénite, France
| | - David Barthelemy
- Center for Innovation in Cancerology of Lyon (CICLY) EA 3738, Faculty of Medicine and Maieutic Lyon Sud, Claude Bernard University Lyon I, 69921 Oullins, France
- Institute of Pharmaceutical and Biological Sciences (ISPB), Claude Bernard University Lyon I, 69373 Lyon, France
- Department of Biochemistry and Molecular Biology, Lyon-Sud Hospital, Hospices Civils de Lyon, 69495 Pierre-Bénite, France
- Circulating Cancer (CIRCAN) Program, Hospices Civils de Lyon, Cancer Institute, 69495 Pierre-Bénite, France
| | - Nazim Benzerdjeb
- Center for Innovation in Cancerology of Lyon (CICLY) EA 3738, Faculty of Medicine and Maieutic Lyon Sud, Claude Bernard University Lyon I, 69921 Oullins, France
- Pathology Department, Claude Bernard University Lyon I, Hospices Civils de Lyon, 69677 Bron, France
| | - Christine Haon
- Center for Innovation in Cancerology of Lyon (CICLY) EA 3738, Faculty of Medicine and Maieutic Lyon Sud, Claude Bernard University Lyon I, 69921 Oullins, France
- Department of Biochemistry and Molecular Biology, Lyon-Sud Hospital, Hospices Civils de Lyon, 69495 Pierre-Bénite, France
- Circulating Cancer (CIRCAN) Program, Hospices Civils de Lyon, Cancer Institute, 69495 Pierre-Bénite, France
| | - Florence Geiguer
- Center for Innovation in Cancerology of Lyon (CICLY) EA 3738, Faculty of Medicine and Maieutic Lyon Sud, Claude Bernard University Lyon I, 69921 Oullins, France
- Institute of Pharmaceutical and Biological Sciences (ISPB), Claude Bernard University Lyon I, 69373 Lyon, France
- Department of Biochemistry and Molecular Biology, Lyon-Sud Hospital, Hospices Civils de Lyon, 69495 Pierre-Bénite, France
- Circulating Cancer (CIRCAN) Program, Hospices Civils de Lyon, Cancer Institute, 69495 Pierre-Bénite, France
| | - Margaux Raffin
- Center for Innovation in Cancerology of Lyon (CICLY) EA 3738, Faculty of Medicine and Maieutic Lyon Sud, Claude Bernard University Lyon I, 69921 Oullins, France
- Institute of Pharmaceutical and Biological Sciences (ISPB), Claude Bernard University Lyon I, 69373 Lyon, France
- Department of Biochemistry and Molecular Biology, Lyon-Sud Hospital, Hospices Civils de Lyon, 69495 Pierre-Bénite, France
- Circulating Cancer (CIRCAN) Program, Hospices Civils de Lyon, Cancer Institute, 69495 Pierre-Bénite, France
| | - Nathalie Hardat
- Belgian Volition SRL, Parc Scientifique Créalys, 5032 Isnes, Belgium
| | - Julie Balandier
- Center for Innovation in Cancerology of Lyon (CICLY) EA 3738, Faculty of Medicine and Maieutic Lyon Sud, Claude Bernard University Lyon I, 69921 Oullins, France
- Institute of Pharmaceutical and Biological Sciences (ISPB), Claude Bernard University Lyon I, 69373 Lyon, France
- Department of Biochemistry and Molecular Biology, Lyon-Sud Hospital, Hospices Civils de Lyon, 69495 Pierre-Bénite, France
- Circulating Cancer (CIRCAN) Program, Hospices Civils de Lyon, Cancer Institute, 69495 Pierre-Bénite, France
| | - Rémi Rabeuf
- Belgian Volition SRL, Parc Scientifique Créalys, 5032 Isnes, Belgium
| | - Lara Chalabreysse
- Pathology Department, Claude Bernard University Lyon I, Hospices Civils de Lyon, 69677 Bron, France
| | - Anne-Sophie Wozny
- Department of Biochemistry and Molecular Biology, Lyon-Sud Hospital, Hospices Civils de Lyon, 69495 Pierre-Bénite, France
- Circulating Cancer (CIRCAN) Program, Hospices Civils de Lyon, Cancer Institute, 69495 Pierre-Bénite, France
- Cellular and Molecular Radiobiology Laboratory UMR CNRS5822/IP2I, Faculty of Medicine and Maieutic Lyon Sud, Claude Bernard University Lyon I, 69921 Oullins, France
| | | | - Claire Rodriguez-Lafrasse
- Department of Biochemistry and Molecular Biology, Lyon-Sud Hospital, Hospices Civils de Lyon, 69495 Pierre-Bénite, France
- Circulating Cancer (CIRCAN) Program, Hospices Civils de Lyon, Cancer Institute, 69495 Pierre-Bénite, France
- Cellular and Molecular Radiobiology Laboratory UMR CNRS5822/IP2I, Faculty of Medicine and Maieutic Lyon Sud, Claude Bernard University Lyon I, 69921 Oullins, France
| | - Fabien Subtil
- Statistic Department, Hospices Civils de Lyon, 69008 Lyon, France
- LBBE, Claude Bernard University Lyon I, UMR 5558, CNRS, 69100 Villeurbanne, France
| | - Sébastien Couraud
- Center for Innovation in Cancerology of Lyon (CICLY) EA 3738, Faculty of Medicine and Maieutic Lyon Sud, Claude Bernard University Lyon I, 69921 Oullins, France
- Pulmonology Department, Lyon Sud Hospital, Hospices Civils de Lyon, 69495 Pierre-Bénite, France
| | - Marielle Herzog
- Belgian Volition SRL, Parc Scientifique Créalys, 5032 Isnes, Belgium
| | - Lea Payen-Gay
- Center for Innovation in Cancerology of Lyon (CICLY) EA 3738, Faculty of Medicine and Maieutic Lyon Sud, Claude Bernard University Lyon I, 69921 Oullins, France
- Institute of Pharmaceutical and Biological Sciences (ISPB), Claude Bernard University Lyon I, 69373 Lyon, France
- Department of Biochemistry and Molecular Biology, Lyon-Sud Hospital, Hospices Civils de Lyon, 69495 Pierre-Bénite, France
- Circulating Cancer (CIRCAN) Program, Hospices Civils de Lyon, Cancer Institute, 69495 Pierre-Bénite, France
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22
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Castellani G, Buccarelli M, Arasi MB, Rossi S, Pisanu ME, Bellenghi M, Lintas C, Tabolacci C. BRAF Mutations in Melanoma: Biological Aspects, Therapeutic Implications, and Circulating Biomarkers. Cancers (Basel) 2023; 15:4026. [PMID: 37627054 PMCID: PMC10452867 DOI: 10.3390/cancers15164026] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 08/03/2023] [Accepted: 08/07/2023] [Indexed: 08/27/2023] Open
Abstract
Melanoma is an aggressive form of skin cancer resulting from the malignant transformation of melanocytes. Recent therapeutic approaches, including targeted therapy and immunotherapy, have improved the prognosis and outcome of melanoma patients. BRAF is one of the most frequently mutated oncogenes recognised in melanoma. The most frequent oncogenic BRAF mutations consist of a single point mutation at codon 600 (mostly V600E) that leads to constitutive activation of the BRAF/MEK/ERK (MAPK) signalling pathway. Therefore, mutated BRAF has become a useful target for molecular therapy and the use of BRAF kinase inhibitors has shown promising results. However, several resistance mechanisms invariably develop leading to therapeutic failure. The aim of this manuscript is to review the role of BRAF mutational status in the pathogenesis of melanoma and its impact on differentiation and inflammation. Moreover, this review focuses on the mechanisms responsible for resistance to targeted therapies in BRAF-mutated melanoma and provides an overview of circulating biomarkers including circulating tumour cells, circulating tumour DNA, and non-coding RNAs.
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Affiliation(s)
- Giorgia Castellani
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy; (G.C.); (M.B.); (M.B.A.); (S.R.)
| | - Mariachiara Buccarelli
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy; (G.C.); (M.B.); (M.B.A.); (S.R.)
| | - Maria Beatrice Arasi
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy; (G.C.); (M.B.); (M.B.A.); (S.R.)
| | - Stefania Rossi
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy; (G.C.); (M.B.); (M.B.A.); (S.R.)
| | - Maria Elena Pisanu
- High Resolution NMR Unit, Core Facilities, Istituto Superiore di Sanità, 00161 Rome, Italy;
| | - Maria Bellenghi
- Center for Gender-Specific Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy;
| | - Carla Lintas
- Research Unit of Medical Genetics, Department of Medicine, Università Campus Bio-Medico di Roma, 00128 Rome, Italy;
- Operative Research Unit of Medical Genetics, Fondazione Policlinico Universitario Campus Bio-Medico, 00128 Rome, Italy
| | - Claudio Tabolacci
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy; (G.C.); (M.B.); (M.B.A.); (S.R.)
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23
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Greten TF, Schwabe R, Bardeesy N, Ma L, Goyal L, Kelley RK, Wang XW. Immunology and immunotherapy of cholangiocarcinoma. Nat Rev Gastroenterol Hepatol 2023; 20:349-365. [PMID: 36697706 DOI: 10.1038/s41575-022-00741-4] [Citation(s) in RCA: 86] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/23/2022] [Indexed: 01/27/2023]
Abstract
Cholangiocarcinoma is the second most common primary liver cancer. Its incidence is low in the Western world but is rising globally. Surgery, chemotherapy and radiation therapy have been the only treatment options for decades. Progress in our molecular understanding of the disease and the identification of druggable targets, such as IDH1 mutations and FGFR2 fusions, has provided new treatment options. Immunotherapy has emerged as a potent strategy for many different types of cancer and has shown efficacy in combination with chemotherapy for cholangiocarcinoma. In this Review, we discuss findings related to key immunological aspects of cholangiocarcinoma, including the heterogeneous landscape of immune cells within the tumour microenvironment, the immunomodulatory effect of the microbiota and IDH1 mutations, and the association of immune-related signatures and patient outcomes. We introduce findings from preclinical immunotherapy studies, discuss future immune-mediated treatment options, and provide a summary of results from clinical trials testing immune-based approaches in patients with cholangiocarcinoma. This Review provides a thorough survey of our knowledge on immune signatures and immunotherapy in cholangiocarcinoma.
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Affiliation(s)
- Tim F Greten
- Gastrointestinal Malignancies Section, Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
- Liver Cancer Program, Bethesda, MD, USA.
| | - Robert Schwabe
- Institute of Human Nutrition, Columbia University, New York, NY, USA
- Department of Medicine, Columbia University, New York, NY, USA
| | - Nabeel Bardeesy
- Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA
- Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Lichun Ma
- Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Lipika Goyal
- Division of Oncology, Stanford School of Medicine, Palo Alto, CA, USA
| | - Robin K Kelley
- Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA
| | - Xin W Wang
- Liver Cancer Program, Bethesda, MD, USA
- Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
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24
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Ravi A, Hellmann MD, Arniella MB, Holton M, Freeman SS, Naranbhai V, Stewart C, Leshchiner I, Kim J, Akiyama Y, Griffin AT, Vokes NI, Sakhi M, Kamesan V, Rizvi H, Ricciuti B, Forde PM, Anagnostou V, Riess JW, Gibbons DL, Pennell NA, Velcheti V, Digumarthy SR, Mino-Kenudson M, Califano A, Heymach JV, Herbst RS, Brahmer JR, Schalper KA, Velculescu VE, Henick BS, Rizvi N, Jänne PA, Awad MM, Chow A, Greenbaum BD, Luksza M, Shaw AT, Wolchok J, Hacohen N, Getz G, Gainor JF. Genomic and transcriptomic analysis of checkpoint blockade response in advanced non-small cell lung cancer. Nat Genet 2023; 55:807-819. [PMID: 37024582 PMCID: PMC10181943 DOI: 10.1038/s41588-023-01355-5] [Citation(s) in RCA: 77] [Impact Index Per Article: 38.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 02/24/2023] [Indexed: 04/08/2023]
Abstract
Anti-PD-1/PD-L1 agents have transformed the treatment landscape of advanced non-small cell lung cancer (NSCLC). To expand our understanding of the molecular features underlying response to checkpoint inhibitors in NSCLC, we describe here the first joint analysis of the Stand Up To Cancer-Mark Foundation cohort, a resource of whole exome and/or RNA sequencing from 393 patients with NSCLC treated with anti-PD-(L)1 therapy, along with matched clinical response annotation. We identify a number of associations between molecular features and outcome, including (1) favorable (for example, ATM altered) and unfavorable (for example, TERT amplified) genomic subgroups, (2) a prominent association between expression of inducible components of the immunoproteasome and response and (3) a dedifferentiated tumor-intrinsic subtype with enhanced response to checkpoint blockade. Taken together, results from this cohort demonstrate the complexity of biological determinants underlying immunotherapy outcomes and reinforce the discovery potential of integrative analysis within large, well-curated, cancer-specific cohorts.
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Affiliation(s)
- Arvind Ravi
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA
- Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | | | - Monica B Arniella
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA
| | - Mark Holton
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA
| | - Samuel S Freeman
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA
| | - Vivek Naranbhai
- Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, MA, USA
- Dana-Farber Cancer Institute, Boston, MA, USA
- Center for the AIDS Programme for Research in South Africa, Durban, South Africa
- Center for Thoracic Cancers, Massachusetts General Hospital, Boston, MA, USA
| | - Chip Stewart
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA
| | - Ignaty Leshchiner
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA
| | | | - Yo Akiyama
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA
| | - Aaron T Griffin
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
- Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Natalie I Vokes
- Department of Thoracic and Head and Neck Oncology, MD Anderson Cancer Center, Houston, TX, USA
- Department of Genomic Medicine, MD Anderson Cancer Center, Houston, TX, USA
| | - Mustafa Sakhi
- Center for Thoracic Cancers, Massachusetts General Hospital, Boston, MA, USA
| | - Vashine Kamesan
- Center for Thoracic Cancers, Massachusetts General Hospital, Boston, MA, USA
| | - Hira Rizvi
- Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Biagio Ricciuti
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Patrick M Forde
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Valsamo Anagnostou
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | | | - Don L Gibbons
- Department of Thoracic and Head and Neck Oncology, MD Anderson Cancer Center, Houston, TX, USA
| | - Nathan A Pennell
- Department of Hematology and Medical Oncology, Cleveland Clinic, Cleveland, OH, USA
| | - Vamsidhar Velcheti
- Department of Hematology and Oncology, NYU Langone Health, New York, NY, USA
| | - Subba R Digumarthy
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Department of Radiology, Massachusetts General Hospital, Boston, MA, USA
| | - Mari Mino-Kenudson
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
| | - Andrea Califano
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
- Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA
- Department of Biomedical Informatics, Columbia University, New York, NY, USA
- Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
- J.P. Sulzberger Columbia Genome Center, New York, NY, USA
| | - John V Heymach
- Department of Thoracic and Head and Neck Oncology, MD Anderson Cancer Center, Houston, TX, USA
| | - Roy S Herbst
- Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA
| | - Julie R Brahmer
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Kurt A Schalper
- Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA
- Department of Pathology, Yale School of Medicine, New Haven, CT, USA
| | - Victor E Velculescu
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Brian S Henick
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | | | - Pasi A Jänne
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Mark M Awad
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Andrew Chow
- Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Benjamin D Greenbaum
- Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Physiology, Biophysics & Systems Biology, Weill Cornell Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Marta Luksza
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Alice T Shaw
- Center for Thoracic Cancers, Massachusetts General Hospital, Boston, MA, USA
| | | | - Nir Hacohen
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA.
- Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, MA, USA.
- Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
| | - Gad Getz
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA.
- Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, MA, USA.
- Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
- Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
| | - Justin F Gainor
- Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, MA, USA.
- Center for Thoracic Cancers, Massachusetts General Hospital, Boston, MA, USA.
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25
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Farahmand Y, Tehrany PM, Nazari A, Nava ZH, Alsaffar MF, Yazdani O, Adili A, Esbati R, Ghafouri K. A comprehensive survey into the role of exosomes in pancreatic cancer; from the origin of cancer to the progress and possibility of diagnosis and treatment. Pathol Res Pract 2023; 245:154465. [PMID: 37119731 DOI: 10.1016/j.prp.2023.154465] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 04/09/2023] [Accepted: 04/12/2023] [Indexed: 05/01/2023]
Abstract
Pancreatic cancer is the fourth most common malignant tumor in the world, which has a high mortality rate due to high invasiveness, early metastases, lack of specific symptoms, and high invasiveness. Recent studies have shown that exosomes can be essential sources of biomarkers in pancreatic cancer. Over the past ten years, exosomes have been implicated in multiple trials to prevent the growth and metastasis of many cancers, including pancreatic cancer. Exosomes also play essential roles in immune evasion, invasion, metastasis, proliferation, apoptosis, drug resistance, and cancer stemness. Exosomes help cells communicate by carrying proteins and genetic material, such as non-coding RNAs, including mRNAs and microRNAs. This review examines the biological significance of exosomes in pancreatic cancer and their functions in tumor invasion, metastasis, treatment resistance, proliferation, stemness, and immune evasion. We also emphasize recent advances in our understanding of the main functions of exosomes in diagnosing and treating pancreatic cancer.
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Affiliation(s)
- Yalda Farahmand
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Pooya M Tehrany
- Faculty of Medicine, National University of Malaysia, Bani, Malaysia
| | - Ahmad Nazari
- Tehran University of Medical Sciences, Tehran, Iran
| | | | - Marwa Fadhil Alsaffar
- Medical Laboratories Techniques Department, Al-Mustaqbal University College, 51001 Hillah, Babil, Iraq
| | - Omid Yazdani
- Department of Medicine, Shahid Beheshti University, Tehran, Iran
| | - Ali Adili
- Tabriz University of Medical Sciences, Tabriz, Iran
| | - Romina Esbati
- Department of Medicine, Shahid Beheshti University, Tehran, Iran.
| | - Kimia Ghafouri
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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26
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Shi Y, Niu Y, Yuan Y, Li K, Zhong C, Qiu Z, Li K, Lin Z, Yang Z, Zuo D, Qiu J, He W, Wang C, Liao Y, Wang G, Yuan Y, Li B. PRMT3-mediated arginine methylation of IGF2BP1 promotes oxaliplatin resistance in liver cancer. Nat Commun 2023; 14:1932. [PMID: 37024475 PMCID: PMC10079833 DOI: 10.1038/s41467-023-37542-5] [Citation(s) in RCA: 50] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 03/22/2023] [Indexed: 04/08/2023] Open
Abstract
Although oxaliplatin-based chemotherapy has been effective in the treatment of hepatocellular carcinoma (HCC), primary or acquired resistance to oxaliplatin remains a major challenge in the clinic. Through functional screening using CRISPR/Cas9 activation library, transcriptomic profiling of clinical samples, and functional validation in vitro and in vivo, we identify PRMT3 as a key driver of oxaliplatin resistance. Mechanistically, PRMT3-mediated oxaliplatin-resistance is in part dependent on the methylation of IGF2BP1 at R452, which is critical for the function of IGF2BP1 in stabilizing the mRNA of HEG1, an effector of PRMT3-IGF2BP1 axis. Also, PRMT3 overexpression may serve as a biomarker for oxaliplatin resistance in HCC patients. Collectively, our study defines the PRTM3-IGF2BP1-HEG1 axis as important regulators and therapeutic targets in oxaliplatin-resistance and suggests the potential to use PRMT3 expression level in pretreatment biopsy as a biomarker for oxaliplatin-resistance in HCC patients.
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Affiliation(s)
- Yunxing Shi
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Yi Niu
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Yichuan Yuan
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Kai Li
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Chengrui Zhong
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Zhiyu Qiu
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Keren Li
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Zhu Lin
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Zhiwen Yang
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Dinglan Zuo
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Jiliang Qiu
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Wei He
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Chenwei Wang
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Yadi Liao
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Guocan Wang
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Yunfei Yuan
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, China.
| | - Binkui Li
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, China.
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Gao Y, Su Z, Wang C, Xu J, Hu S, Zhang C, Sun P, Zhou X, Wang W, Zou T, Yang B, Cheng X, Yi X, Zheng Q. Light-triggered polymeric prodrug and nano-assembly for chemo-photodynamic therapy and potentiate immune checkpoint blockade immunotherapy for hepatocellular carcinoma. MATERIALS & DESIGN 2023; 225:111457. [DOI: 10.1016/j.matdes.2022.111457] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/05/2024]
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Vo T, Saini Y. Case report: Mafb promoter activity may define the alveolar macrophage dichotomy. Front Immunol 2022; 13:1050494. [PMID: 36578483 PMCID: PMC9791191 DOI: 10.3389/fimmu.2022.1050494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 11/25/2022] [Indexed: 12/14/2022] Open
Abstract
Cre-LoxP system has been widely used to induce recombination of floxed genes of interest. Currently available macrophage promoter-specific Cre recombinase mice strains have various limitations that warrants the testing of additional Cre strains. V-maf musculoaponeurotic fibrosarcoma oncogene family, protein b -Cre (Mafb-Cre) mice label macrophages in most organs such as spleen, small intestine, lung, bone marrow, and peritoneal cavity. However, whether Mafb-Cre recombinase targets the gene recombination in alveolar macrophage remains untested. Here, we utilized MafbCre/WTR26mTmG/WT strain that expresses mTOM protein in all the cells of mouse body except for those that express Mafb-Cre-regulated mEGFP. We performed fluorescent microscopy and flow cytometry to analyze mTOM and mEGFP expression in alveolar macrophages from MafbCre/WTR26mTmG/WT mice. Our analyses revealed that the Mafb-Cre is active in only ~40% of the alveolar macrophages in an age-independent manner. While Mafb- (mTOM+/mEGFP-) and Mafb+ (mEGFP+) alveolar macrophages exhibit comparable expression of CD11b and CD11c surface markers, the surface expression of MHCII is elevated in the Mafb+ (mEGFP+) macrophages. The bone marrow-derived macrophages from MafbCre/WTR26mTmG/WT mice are highly amenable to Cre-LoxP recombination in vitro. The bone marrow depletion and reconstitution experiment revealed that ~98% of alveolar macrophages from MafbCre/WTR26mTmG/WT → WT chimera are amenable to the Mafb-Cre-mediated recombination. Finally, the Th2 stimulation and ozone exposure to the MafbCre/WTR26mTmG/WT mice promote the Mafb-Cre-mediated recombination in alveolar macrophages. In conclusion, while the Mafb-/Mafb+ dichotomy thwarts the use of Mafb-Cre for the induction of floxed alleles in the entire alveolar macrophage population, this strain provides a unique tool to induce gene deletion in alveolar macrophages that encounter Th2 microenvironment in the lung airspaces.
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Shah UJ, Alsulimani A, Ahmad F, Mathkor DM, Alsaieedi A, Harakeh S, Nasiruddin M, Haque S. Bioplatforms in liquid biopsy: advances in the techniques for isolation, characterization and clinical applications. Biotechnol Genet Eng Rev 2022; 38:339-383. [PMID: 35968863 DOI: 10.1080/02648725.2022.2108994] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Tissue biopsy analysis has conventionally been the gold standard for cancer prognosis, diagnosis and prediction of responses/resistances to treatments. The existing biopsy procedures used in clinical practice are, however, invasive, painful and often associated with pitfalls like poor recovery of tumor cells and infeasibility for repetition in single patients. To circumvent these limitations, alternative non-invasive, rapid and economical, yet sturdy, consistent and dependable, biopsy techniques are required. Liquid biopsy is an emerging technology that fulfills these criteria and potentially much more in terms of subject-specific real-time monitoring of cancer progression, determination of tumor heterogeneity and treatment responses, and specific identification of the type and stages of cancers. The present review first briefly revisits the state-of-the-art technique of liquid biopsy and then proceeds to address in detail, the advances in the potential clinical applications of four major biological agencies present in liquid biopsy samples (circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), exosomes and tumor-educated platelets (TEPs)). Finally, the authors conclude with the limitations that need to be addressed in order for liquid biopsy to effectively replace the conventional invasive biopsy methods in the clinical settings.
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Affiliation(s)
- Ushma Jaykamal Shah
- MedGenome Labs Ltd, Kailash Cancer Hospital and Research Center, Vadodara, India
| | - Ahmad Alsulimani
- Medical Laboratory Technology Department, College of Applied Medical Sciences, Jazan University, Jazan, Saudi Arabia
| | - Faraz Ahmad
- Department of Biotechnology, School of Bio Sciences and Technology (SBST), Vellore Institute of Technology, Vellore, India
| | - Darin Mansor Mathkor
- Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan, Saudi Arabia
| | - Ahdab Alsaieedi
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.,Vaccines and Immunotherapy Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Steve Harakeh
- King Fahd Medical Research Center, and Yousef Abdullatif Jameel Chair of Prophetic Medicine Application, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mohammad Nasiruddin
- MedGenome Labs Ltd, Narayana Health City, Bangalore, India.,Genomics Lab, Orbito Asia Diagnostics, Coimbatore, India
| | - Shafiul Haque
- Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan, Saudi Arabia
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Jiang L, Lyu Q, Abdelhamid AMH, Hui S, Sheng K. An efficient rectangular optimization method for sparse orthogonal collimator based small animal irradiation. Phys Med Biol 2022; 67:10.1088/1361-6560/ac910b. [PMID: 36084625 PMCID: PMC9595432 DOI: 10.1088/1361-6560/ac910b] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 09/09/2022] [Indexed: 11/11/2022]
Abstract
Objective.Intensity-modulated radiotherapy (IMRT) is widely used in clinical radiotherapy, treating varying malignancies with conformal doses. As the test field for clinical translation, preclinical small animal experiments need to mimic the human radiotherapy condition, including IMRT. However, small animal IMRT is a systematic challenge due to the lack of corresponding hardware and software for miniaturized targets.Approach.The sparse orthogonal collimators (SOC) based on the direct rectangular aperture optimization (RAO) substantially simplified the hardware for miniaturization. This study investigates and evaluates a significantly improved RAO algorithm for complex mouse irradiation using SOC. Because the Kronecker product representation of the rectangular aperture is the main limitation of the computational performance, we reformulated matrix multiplication in the data fidelity term using multiplication with small matrices instead of the Kronecker product of the dose loading matrices. Solving the optimization problem was further accelerated using the Fast Iterative Shrinkage-Thresholding Algorithm (FISTA).Main results.Four mouse cases, including a liver, a brain tumor, a concave U-target, and a complex total marrow irradiation (TMI) case, were included in this study with manually delineated targets and OARs. Seven coplanar-field SOC IMRT (sIMRT) plans were compared with idealistic fluence map based IMRT (iIMRT) plans. For the first three cases with simpler and smaller targets, the differences between sIMRT plans and iIMRT plans in the planning target volumes (PTV) statistics are within 1%. For the TMI case, the sIMRT plans are superior in reducing hot spots (also termedDmax) of PTV, kidneys, lungs, heart, and bowel by 20.5%, 31.5%, 24.67%, 20.13%, and 17.78%, respectively. On average, in four cases in this study, the sIMRT plan conformity is comparable to that of the iIMRT's with lightly increased R50 and Integral Dose by 2.23% and 2.78%.Significance.The significantly improved sIMRT optimization method allows fast plan creation in under 1 min for smaller targets and makes complex TMI planning feasible while achieving comparable dosimetry to idealistic IMRT with fluence map optimization.
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Affiliation(s)
- Lu Jiang
- Department of Radiation Oncology, University of California Los Angeles, Los Angeles, CA, United States of America
| | - Qihui Lyu
- Department of Radiation Oncology, University of California Los Angeles, Los Angeles, CA, United States of America
| | - Amr M H Abdelhamid
- Department of Radiation Oncology, City of Hope Medical Center, Duarte, CA, United States of America
| | - Susanta Hui
- Department of Radiation Oncology, City of Hope Medical Center, Duarte, CA, United States of America
| | - Ke Sheng
- Department of Radiation Oncology, University of California Los Angeles, Los Angeles, CA, United States of America
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Ghatak S, Hascall VC, Karamanos N, Markwald RR, Misra S. Interplay Between Chemotherapy-Activated Cancer Associated Fibroblasts and Cancer Initiating Cells Expressing CD44v6 Promotes Colon Cancer Resistance. Front Oncol 2022; 12:906415. [PMID: 35982950 PMCID: PMC9380598 DOI: 10.3389/fonc.2022.906415] [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: 03/28/2022] [Accepted: 06/22/2022] [Indexed: 11/14/2022] Open
Abstract
Cancer-initiating cells (CICs) drive colorectal tumor growth by their supportive niches where CICs interact with multiple cell types within the microenvironment, including cancer-associated fibroblasts (CAFs). We investigated the interplay between the CICs and the clinically relevant chemotherapeutic FOLFOX that creates the persistent tumorigenic properties of colorectal CICs, and stimulates the microenvironmental factors derived from the CAFs. We found that the CICs expressing an immunophenotype (CD44v6[+]) promote FOLFOX-resistance and that the CIC-immunophenotype was enhanced by factors secreted by CAFs after FOLFOX treatment These secreted factors included periostin, IL17A and WNT3A, which induced CD44v6 expression by activating WNT3A/β-catenin signaling. Blocking the interaction between CICs with any of these CAF-derived factors through tissue-specific conditional silencing of CD44v6 significantly reduced colorectal tumorigenic potential. To achieve this, we generated two unique vectors (floxed-pSico-CD44v6 shRNA plus Fabpl-Cre) that were encapsulated into transferrin coated PEG-PEI/(nanoparticles), which when introduced in vivo reduced tumor growth more effectively than using CD44v6-blocking antibodies. Notably, this tissue-specific conditional silencing of CD44v6 resulted in long lasting effects on self-renewal and tumor growth associated with a positive feedback loop linking WNT3A signaling and alternative-splicing of CD44. These findings have crucial clinical implications suggesting that therapeutic approaches for modulating tumor growth that currently focus on cell-autonomous mechanisms may be too limited and need to be broadened to include mechanisms that recognize the interplay between the stromal factors and the subsequent CIC-immunophenotype enrichment. Thus, more specific therapeutic approaches may be required to block a chemotherapy induced remodeling of a microenvironment that acts as a paracrine regulator to enrich CD44v6 (+) in colorectal CICs.
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Affiliation(s)
- Shibnath Ghatak
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, United States
- Department Natural Sciences, Trident Technical College, North Charleston, SC, United States
| | - Vincent C. Hascall
- Department of Biomedical Engineering/ND20, Cleveland Clinic, Cleveland, OH, United States
| | - Nikos Karamanos
- Department of Chemistry, University of Patras, Matrix Pathobiology Research Group, Patras, Greece
| | - Roger R. Markwald
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, United States
| | - Suniti Misra
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, United States
- Department Natural Sciences, Trident Technical College, North Charleston, SC, United States
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Falletta P, Goding CR, Vivas-García Y. Connecting Metabolic Rewiring With Phenotype Switching in Melanoma. Front Cell Dev Biol 2022; 10:930250. [PMID: 35912100 PMCID: PMC9334657 DOI: 10.3389/fcell.2022.930250] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 06/24/2022] [Indexed: 11/13/2022] Open
Abstract
Melanoma is a complex and aggressive cancer type that contains different cell subpopulations displaying distinct phenotypes within the same tumor. Metabolic reprogramming, a hallmark of cell transformation, is essential for melanoma cells to adopt different phenotypic states necessary for adaptation to changes arising from a dynamic milieu and oncogenic mutations. Increasing evidence demonstrates how melanoma cells can exhibit distinct metabolic profiles depending on their specific phenotype, allowing adaptation to hostile microenvironmental conditions, such as hypoxia or nutrient depletion. For instance, increased glucose consumption and lipid anabolism are associated with proliferation, while a dependency on exogenous fatty acids and an oxidative state are linked to invasion and metastatic dissemination. How these different metabolic dependencies are integrated with specific cell phenotypes is poorly understood and little is known about metabolic changes underpinning melanoma metastasis. Recent evidence suggests that metabolic rewiring engaging transitions to invasion and metastatic progression may be dependent on several factors, such as specific oncogenic programs or lineage-restricted mechanisms controlling cell metabolism, intra-tumor microenvironmental cues and anatomical location of metastasis. In this review we highlight how the main molecular events supporting melanoma metabolic rewiring and phenotype-switching are parallel and interconnected events that dictate tumor progression and metastatic dissemination through interplay with the tumor microenvironment.
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Affiliation(s)
- Paola Falletta
- Vita-Salute San Raffaele University, Milan, Italy
- Experimental Imaging Center, IRCCS Ospedale San Raffaele, Milan, Italy
- *Correspondence: Paola Falletta, ; Colin R. Goding, ; Yurena Vivas-García, ,
| | - Colin R. Goding
- Nuffield Department of Clinical Medicine, Ludwig Cancer Research, University of Oxford, Oxford, United Kingdom
- *Correspondence: Paola Falletta, ; Colin R. Goding, ; Yurena Vivas-García, ,
| | - Yurena Vivas-García
- Nuffield Department of Clinical Medicine, Ludwig Cancer Research, University of Oxford, Oxford, United Kingdom
- *Correspondence: Paola Falletta, ; Colin R. Goding, ; Yurena Vivas-García, ,
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Ham L, Coomer M, Stumpf M. The chemical Langevin equation for biochemical systems in dynamic environments. J Chem Phys 2022; 157:094105. [DOI: 10.1063/5.0095840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Modelling and simulation of complex biochemical reaction networks form cornerstones of modern biophysics. Many of the approaches developed so far capture temporal fluctuations due to the inherent stochasticity of the biophysical processes, referred to as intrinsic noise. Stochastic fluctuations, however, predominantly stem from the interplay of the network with many other - and mostly unknown - fluctuating processes, as well as with various random signals arising from the extracellular world; these sources contribute extrinsic noise. Here we provide a computational simulation method to probe the stochastic dynamics of biochemical systems subject to both intrinsic and extrinsic noise. We develop an extrinsic chemical Langevin equation-a physically motivated extension of the chemical Langevin equation- to model intrinsically noisy reaction networks embedded in a stochastically fluctuating environment. The extrinsic CLE is a continuous approximation to the Chemical Master Equation (CME) with time-varying propensities. In our approach, noise is incorporated at the level of the CME, and can account for the full dynamics of the exogenous noise process, irrespective of timescales and their mismatches. We show that our method accurately captures the first two moments of the stationary probability density when compared with exact stochastic simulation methods, while reducing the computational runtime by several orders of magnitude. Our approach provides a method that is practical, computationally efficient and physically accurate to study systems that are simultaneously subject to a variety of noise sources.
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Affiliation(s)
- Lucy Ham
- The University of Melbourne, University of Melbourne, Australia
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Joshi S, Sharabi A. Targeting myeloid-derived suppressor cells to enhance natural killer cell-based immunotherapy. Pharmacol Ther 2022; 235:108114. [DOI: 10.1016/j.pharmthera.2022.108114] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 01/06/2022] [Accepted: 01/11/2022] [Indexed: 12/09/2022]
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Brutovský B. Scales of Cancer Evolution: Selfish Genome or Cooperating Cells? Cancers (Basel) 2022; 14:cancers14133253. [PMID: 35805025 PMCID: PMC9264996 DOI: 10.3390/cancers14133253] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 06/22/2022] [Accepted: 06/29/2022] [Indexed: 11/25/2022] Open
Abstract
Simple Summary Cancer continuously evolves its ability to survive in time-varying microenvironment, which results, regarding the therapeutic context, in its therapeutic resistance. As it is accepted that the development of resistance is the direct consequence of intratumour heterogeneity, its evolutionary etiology is intensively studied. Models of carinogenesis are often assessed accordingly to how well they fit into the evolutionary scenario. In the paper, the relevant observations and concepts in cancer research, such as intratumour heterogeneity, cell plasticity, and Markov cell state dynamics, are reviewed and integrated into an evolutionary model. The possibility that the interaction between cancer cells can be interpreted as cooperation is proposed. Abstract The exploitation of the evolutionary modus operandi of cancer to steer its progression towards drug sensitive cancer cells is a challenging research topic. Integrating evolutionary principles into cancer therapy requires properly identified selection level, the relevant timescale, and the respective fitness of the principal selection unit on that timescale. Interpretation of some features of cancer progression, such as increased heterogeneity of isogenic cancer cells, is difficult from the most straightforward evolutionary view with the cancer cell as the principal selection unit. In the paper, the relation between the two levels of intratumour heterogeneity, genetic, due to genetic instability, and non-genetic, due to phenotypic plasticity, is reviewed and the evolutionary role of the latter is outlined. In analogy to the evolutionary optimization in a changing environment, the cell state dynamics in cancer clones are interpreted as the risk diversifying strategy bet hedging, optimizing the balance between the exploitation and exploration of the cell state space.
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Affiliation(s)
- Branislav Brutovský
- Department of Biophysics, Faculty of Science, P. J. Šafárik University, Jesenná 5, 041 54 Košice, Slovakia
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Kim GT, Shin SH, Kim EY, Lee H, Lee SH, Sohn KY, Kim JW. PLAG co-treatment increases the anticancer effect of Adriamycin and cyclophosphamide in a triple-negative breast cancer xenograft mouse model. Biochem Biophys Res Commun 2022; 619:110-116. [PMID: 35753218 DOI: 10.1016/j.bbrc.2022.06.051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 06/09/2022] [Accepted: 06/16/2022] [Indexed: 11/02/2022]
Abstract
Chemotherapy induces tumor cell death and inhibits tumor progression, but the accompanying immune responses in the surrounding dying tissue cause significant inflammation. These responses, such as excessive neutrophil infiltration into tumor tissue, are the main causes of resistance to anticancer treatment. The development of drugs that reduce neutrophil infiltration into tumors is necessary to increase the anticancer effect of chemotherapy. Here, we show that the antitumor effect of the chemotherapy AC regimen (Adriamycin and cyclophosphamide) was increased by 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) cotreatment in the MDA-MB-231 triple-negative breast cancer xenograft mouse model. Tumor growth was inhibited up to 56% in mice treated with AC and inhibited up to 94% in mice cotreated with AC and PLAG. Side effects of chemotherapy, such as a reduction in body weight, were alleviated in mice cotreated with AC and PLAG. Excessive neutrophil infiltration caused by the AC regimen was successfully cleared in mice cotreated with AC and PLAG. We conclude that PLAG inhibits excessive neutrophil infiltration that aids tumor growth. Reduced neutrophils and increased lymphocytes in PLAG-treated mice can maximize the antitumor effect of the AC regimen and inhibit tumor growth.
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Affiliation(s)
- Guen Tae Kim
- Enzychem Lifesciences, 10F aT Center 27 Gangnam-daero, Seoul, South Korea
| | - Su-Hyun Shin
- Enzychem Lifesciences, 10F aT Center 27 Gangnam-daero, Seoul, South Korea
| | - Eun Young Kim
- Enzychem Lifesciences, 10F aT Center 27 Gangnam-daero, Seoul, South Korea
| | - Hyowon Lee
- Enzychem Lifesciences, 10F aT Center 27 Gangnam-daero, Seoul, South Korea
| | - Se Hee Lee
- Enzychem Lifesciences, 10F aT Center 27 Gangnam-daero, Seoul, South Korea
| | - Ki-Young Sohn
- Enzychem Lifesciences, 10F aT Center 27 Gangnam-daero, Seoul, South Korea
| | - Jae Wha Kim
- Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Kwahak-ro, Daejeon, South Korea.
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Ibragimova M, Tsyganov M, Litviakov N. Tumour Stem Cells in Breast Cancer. Int J Mol Sci 2022; 23:ijms23095058. [PMID: 35563449 PMCID: PMC9099719 DOI: 10.3390/ijms23095058] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 04/27/2022] [Accepted: 04/30/2022] [Indexed: 12/12/2022] Open
Abstract
Tumour stem cells (CSCs) are a self-renewing population that plays important roles in tumour initiation, recurrence, and metastasis. Although the medical literature is extensive, problems with CSC identification and cancer therapy remain. This review provides the main mechanisms of CSC action in breast cancer (BC): CSC markers and signalling pathways, heterogeneity, plasticity, and ecological behaviour. The dynamic heterogeneity of CSCs and the dynamic transitions of CSC− non-CSCs and their significance for metastasis are considered.
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Affiliation(s)
- Marina Ibragimova
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 5, Kooperativny Street, 634050 Tomsk, Russia; (M.T.); (N.L.)
- Laboratory of Genetic Technologies, Siberian State Medical University, 2, Moscow Tract, 634050 Tomsk, Russia
- Biological Institute, National Research Tomsk State University, 36, Lenin, 634050 Tomsk, Russia
- Correspondence:
| | - Matvey Tsyganov
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 5, Kooperativny Street, 634050 Tomsk, Russia; (M.T.); (N.L.)
| | - Nikolai Litviakov
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 5, Kooperativny Street, 634050 Tomsk, Russia; (M.T.); (N.L.)
- Laboratory of Genetic Technologies, Siberian State Medical University, 2, Moscow Tract, 634050 Tomsk, Russia
- Biological Institute, National Research Tomsk State University, 36, Lenin, 634050 Tomsk, Russia
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Khare S, Khare T, Ramanathan R, Ibdah JA. Hepatocellular Carcinoma: The Role of MicroRNAs. Biomolecules 2022; 12:biom12050645. [PMID: 35625573 PMCID: PMC9138333 DOI: 10.3390/biom12050645] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Revised: 04/21/2022] [Accepted: 04/25/2022] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. HCC is diagnosed in its advanced stage when limited treatment options are available. Substantial morphologic, genetic and epigenetic heterogeneity has been reported in HCC, which poses a challenge for the development of a targeted therapy. In this review, we discuss the role and involvement of several microRNAs (miRs) in the heterogeneity and metastasis of hepatocellular carcinoma with a special emphasis on their possible role as a diagnostic and prognostic tool in the risk prediction, early detection, and treatment of hepatocellular carcinoma.
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Affiliation(s)
- Sharad Khare
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO 65212, USA; (S.K.); (T.K.); (R.R.)
- Harry S. Truman Veterans Hospital, Columbia, MO 65201, USA
| | - Tripti Khare
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO 65212, USA; (S.K.); (T.K.); (R.R.)
| | - Raghu Ramanathan
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO 65212, USA; (S.K.); (T.K.); (R.R.)
- Harry S. Truman Veterans Hospital, Columbia, MO 65201, USA
| | - Jamal A. Ibdah
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO 65212, USA; (S.K.); (T.K.); (R.R.)
- Harry S. Truman Veterans Hospital, Columbia, MO 65201, USA
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO 65212, USA
- Correspondence: ; Tel.: 1-573-882-7349; Fax: 1-573-884-4595
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Chen T, Kim KY, Oh Y, Jeung HC, Chung KY, Roh MR, Zhang X. Implication of COPB2 Expression on Cutaneous Squamous Cell Carcinoma Pathogenesis. Cancers (Basel) 2022; 14:cancers14082038. [PMID: 35454945 PMCID: PMC9029015 DOI: 10.3390/cancers14082038] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 04/07/2022] [Accepted: 04/15/2022] [Indexed: 01/02/2023] Open
Abstract
Simple Summary The present study aimed to evaluate the effect of COPB2 expression on cutaneous squamous cell carcinoma (cSCC) pathogenesis. cSCC, a common category of skin cancer, is marked by a reasonably favorable prognosis. However, there has been a steady rise in the annual incidence of cases; in particular, a subset of cases showed aggressive progression. However, the underlying molecular mechanism of cSCC pathogenesis is largely unknown. In the present study, we found that COPB2 may act as a potential oncogene and modulator of the tumor immune microenvironment in cSCC pathogenesis. Therefore, COPB2 can serve as a novel predictive prognostic biomarker and immunotherapeutic target in cSCC patients. Abstract The underlying molecular mechanisms of cutaneous squamous cell carcinoma (cSCC) pathogenesis are largely unknown. In the present study, we aimed to evaluate the effect of coatomer protein complex subunit beta 2 (COPB2) expression on cSCC pathogenesis. Clinicopathological significance of COPB2 in cSCC was investigated by analyzing the Gene Expression Omnibus (GEO) database and through a retrospective cohort study of 95 cSCC patients. The effect of COPB2 expression on the biological behavior of cSCC cells was investigated both in vitro and in vivo. We found that COPB2 expression was significantly higher in cSCC samples than in normal skin samples. In our cohort, a considerable association was found between COPB2 expression and indicators of tumor immune microenvironment (TIME), such as histocompatibility complex class (MHC) I, and MHC II, CD4+/ CD8+ tumor-infiltrating lymphocytes. Additionally, COPB2 expression had an independent impact on worsened recurrence-free survival in our cohort. Furthermore, decreased proliferation, invasion, tumorigenic activities, and increased apoptosis were observed after COPB2 knockdown in cSCC cells. COPB2 may act as a potential oncogene and candidate modulator of the TIME in cSCC. Therefore, it can serve as a novel predictive prognostic biomarker and candidate immunotherapeutic target in cSCC patients.
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Affiliation(s)
- Taiqin Chen
- Department of Dermatology, Yanbian University Hospital, Yanji 133000, China;
| | - Ki-Yeol Kim
- Department of Dental Education, BK21 PLuS Project, Yonsei University College of Dentistry, Seoul 03722, Korea;
| | - Yeongjoo Oh
- Department of Dermatology, Yongin Severance Hospital, Yonsei University College of Medicine, Seoul 16995, Korea;
| | - Hei Cheul Jeung
- Cancer Metastasis Research Center, Division of Medical Oncology, Cancer Center Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Korea;
| | - Kee Yang Chung
- Department of Dermatology, Cutaneous Biology Research Institute, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Korea;
| | - Mi Ryung Roh
- Department of Dermatology, Gangnam Severance Hospital, Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul 06273, Korea
- Correspondence: (M.R.R.); (X.Z.); Tel.: +82-2-2019-3360 (M.R.R.); +82-2-2228-3034 (X.Z.)
| | - Xianglan Zhang
- Department of Pathology, Yanbian University Hospital, Yanji 133000, China
- Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul 03722, Korea
- Correspondence: (M.R.R.); (X.Z.); Tel.: +82-2-2019-3360 (M.R.R.); +82-2-2228-3034 (X.Z.)
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Benboubker V, Boivin F, Dalle S, Caramel J. Cancer Cell Phenotype Plasticity as a Driver of Immune Escape in Melanoma. Front Immunol 2022; 13:873116. [PMID: 35432344 PMCID: PMC9012258 DOI: 10.3389/fimmu.2022.873116] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 03/04/2022] [Indexed: 12/15/2022] Open
Abstract
Immunotherapies blocking negative immune checkpoints are now approved for the treatment of a growing number of cancers. However, even in metastatic melanoma, where sustained responses are observed, a significant number of patients still do not respond or display resistance. Increasing evidence indicates that non-genetic cancer cell-intrinsic alterations play a key role in resistance to therapies and immune evasion. Cancer cell plasticity, mainly associated with the epithelial-to-mesenchymal transition in carcinoma, relies on transcriptional, epigenetic or translational reprogramming. In melanoma, an EMT-like dedifferentiation process is characterized by the acquisition of invasive or neural crest stem cell-like features. Herein, we discuss recent findings on the specific roles of phenotypic reprogramming of melanoma cells in driving immune evasion and resistance to immunotherapies. The mechanisms by which dedifferentiated melanoma cells escape T cell lysis, mediate T cell exclusion or remodel the immune microenvironment will be detailed. The expanded knowledge on tumor cell plasticity in melanoma should contribute to the development of novel therapeutic combination strategies to further improve outcomes in this deadly metastatic cancer.
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Affiliation(s)
- Valentin Benboubker
- Cancer Research Center of Lyon, Université de Lyon, Université Claude Bernard Lyon 1, INSERM, CNRS, Centre Léon Bérard, “Cancer cell Plasticity in Melanoma” team, Lyon, France
| | - Félix Boivin
- Cancer Research Center of Lyon, Université de Lyon, Université Claude Bernard Lyon 1, INSERM, CNRS, Centre Léon Bérard, “Cancer cell Plasticity in Melanoma” team, Lyon, France
| | - Stéphane Dalle
- Cancer Research Center of Lyon, Université de Lyon, Université Claude Bernard Lyon 1, INSERM, CNRS, Centre Léon Bérard, “Cancer cell Plasticity in Melanoma” team, Lyon, France
- Dermatology Unit, Hospices Civils de Lyon, CH Lyon Sud, Pierre Bénite Cedex, France
| | - Julie Caramel
- Cancer Research Center of Lyon, Université de Lyon, Université Claude Bernard Lyon 1, INSERM, CNRS, Centre Léon Bérard, “Cancer cell Plasticity in Melanoma” team, Lyon, France
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Turiello R, Capone M, Morretta E, Monti MC, Madonna G, Azzaro R, Del Gaudio P, Simeone E, Sorrentino A, Ascierto PA, Morello S. Exosomal CD73 from serum of patients with melanoma suppresses lymphocyte functions and is associated with therapy resistance to anti-PD-1 agents. J Immunother Cancer 2022; 10:jitc-2021-004043. [PMID: 35273100 PMCID: PMC8915288 DOI: 10.1136/jitc-2021-004043] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/08/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND CD73 is an ectonucleotidase producing the immunosuppressor mediator adenosine. Elevated levels of circulating CD73 in patients with cancer have been associated with disease progression and poor response to immunotherapy. Immunosuppressive pathways associated with exosomes can affect T-cell function and the therapeutic efficacy of anti-programmed cell-death protein 1 (anti-PD-1) therapy. Here, we conducted a retrospective pilot study to evaluate levels of exosomal CD73 before and early during treatment with anti-PD-1 agents in patients with melanoma and its potential contribution to affect T-cell functions and to influence the clinical outcomes of anti-PD-1 monotherapy. METHODS Exosomes were isolated by mini size exclusion chromatography from serum of patients with melanoma (n=41) receiving nivolumab or pembrolizumab monotherapy. Expression of CD73 and programmed death-ligand 1 (PD-L1) were evaluated on exosomes enriched for CD63 by on-bead flow cytometry. The CD73 AMPase activity was evaluated by mass spectrometry, also in the presence of selective inhibitors of CD73. Interferon (IFN)-γ production and granzyme B expression were measured in CD3/28 activated T cells incubated with exosomes in presence of the CD73 substrate AMP. Levels of CD73 and PD-L1 on exosomes were correlated with therapy response. Exosomes isolated from healthy subjects were used as control. RESULTS Isolated exosomes carried CD73 on their surface, which is enzymatically active in producing adenosine. Incubation of exosomes with CD3/28 activated T cells in the presence of AMP resulted in a significant reduction of IFN-γ release, which was reversed by the CD73 inhibitor APCP or by the selective A2A adenosine receptor antagonist ZM241385. Expression levels of exosomal CD73 from serum of patients with melanoma were not significantly different from those in healthy subjects. Early on-treatment, expression levels of both CD73 and PD-L1 on exosomes isolated from patients receiving pembrolizumab or nivolumab monotherapy were significantly increased compared with baseline. Early during therapy exosomal PD-L1 increased in responders, while exosomal CD73 resulted significantly increased in non-responders. CONCLUSIONS CD73 expressed on exosomes from serum of patients with melanoma produces adenosine and contributes to suppress T-cell functions. Early on-treatment, elevated expression levels of exosomal CD73 might affect the response to anti-PD-1 agents in patients with melanoma who failed to respond to therapy.
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Affiliation(s)
- Roberta Turiello
- Department of Pharmacy, University of Salerno, Fisciano, Italy.,PhD Program in Drug Discovery and Development, University of Salerno, Fisciano, Italy
| | | | - Elva Morretta
- Department of Pharmacy, University of Salerno, Fisciano, Italy
| | | | - Gabriele Madonna
- Istituto Nazionale Tumori IRCCS Fondazione G Pascale, Napoli, Italy
| | - Rosa Azzaro
- Istituto Nazionale Tumori IRCCS Fondazione G Pascale, Napoli, Italy
| | | | - Ester Simeone
- Istituto Nazionale Tumori IRCCS Fondazione G Pascale, Napoli, Italy
| | | | - Paolo A Ascierto
- Istituto Nazionale Tumori IRCCS Fondazione G Pascale, Napoli, Italy
| | - Silvana Morello
- Department of Pharmacy, University of Salerno, Fisciano, Italy
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Descamps L, Le Roy D, Deman AL. Microfluidic-Based Technologies for CTC Isolation: A Review of 10 Years of Intense Efforts towards Liquid Biopsy. Int J Mol Sci 2022; 23:ijms23041981. [PMID: 35216097 PMCID: PMC8875744 DOI: 10.3390/ijms23041981] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 02/04/2022] [Accepted: 02/07/2022] [Indexed: 02/01/2023] Open
Abstract
The selection of circulating tumor cells (CTCs) directly from blood as a real-time liquid biopsy has received increasing attention over the past ten years, and further analysis of these cells may greatly aid in both research and clinical applications. CTC analysis could advance understandings of metastatic cascade, tumor evolution, and patient heterogeneity, as well as drug resistance. Until now, the rarity and heterogeneity of CTCs have been technical challenges to their wider use in clinical studies, but microfluidic-based isolation technologies have emerged as promising tools to address these limitations. This review provides a detailed overview of latest and leading microfluidic devices implemented for CTC isolation. In particular, this study details must-have device performances and highlights the tradeoff between recovery and purity. Finally, the review gives a report of CTC potential clinical applications that can be conducted after CTC isolation. Widespread microfluidic devices, which aim to support liquid-biopsy-based applications, will represent a paradigm shift for cancer clinical care in the near future.
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Affiliation(s)
- Lucie Descamps
- Univ Lyon, Université Claude Bernard Lyon 1, CNRS, INSA Lyon, Ecole Centrale de Lyon, CPE Lyon, INL, UMR5270, 69622 Villeurbanne, France;
| | - Damien Le Roy
- Institut Lumière Matière ILM-UMR 5306, CNRS, Université Lyon 1, 69622 Villeurbanne, France;
| | - Anne-Laure Deman
- Univ Lyon, Université Claude Bernard Lyon 1, CNRS, INSA Lyon, Ecole Centrale de Lyon, CPE Lyon, INL, UMR5270, 69622 Villeurbanne, France;
- Correspondence:
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De Matteis R, Flak MB, Gonzalez-Nunez M, Austin-Williams S, Palmas F, Colas RA, Dalli J. Aspirin activates resolution pathways to reprogram T cell and macrophage responses in colitis-associated colorectal cancer. SCIENCE ADVANCES 2022; 8:eabl5420. [PMID: 35108049 PMCID: PMC8809687 DOI: 10.1126/sciadv.abl5420] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 12/08/2021] [Indexed: 05/15/2023]
Abstract
Inflammation is linked with carcinogenesis in many types of cancer including colorectal cancer (CRC). Aspirin is recommended for the prevention of CRC, although the mechanism(s) mediating its immunomodulatory actions remain incompletely understood. Here, we demonstrate that aspirin increased concentrations of the immune-regulatory aspirin-triggered specialized proresolving mediators (AT-SPMs), including AT-lipoxin A4 and AT-resolvin D1, in colonic tissues during inflammation-associated CRC (I-CRC). Aspirin also down-regulated the expression of the checkpoint protein programmed cell death protein-1 in macrophages and CD8+ T cells from the colonic mucosa. Inhibition of AT-SPM biosynthesis or knockout of the AT-SPM receptor Alx/Fpr2 reversed the immunomodulatory actions of aspirin on macrophages and CD8+ T cells and abrogated its protective effects during I-CRC. Furthermore, treatment of mice with AT-SPM recapitulated the immune-directed actions of aspirin during I-CRC. Together, these findings elucidate a central role for AT-SPM in mediating the immune-directed actions of aspirin in regulating I-CRC progression.
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Affiliation(s)
- Roberta De Matteis
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK
| | - Magdalena B. Flak
- Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Maria Gonzalez-Nunez
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK
| | - Shani Austin-Williams
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK
| | - Francesco Palmas
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK
| | - Romain A. Colas
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK
| | - Jesmond Dalli
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK
- Centre for Inflammation and Therapeutic Innovation, Queen Mary University of London, London, UK
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44
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Gameiro SF, Evans AM, Mymryk JS. The tumor immune microenvironments of HPV + and HPV - head and neck cancers. WIREs Mech Dis 2022; 14:e1539. [PMID: 35030304 DOI: 10.1002/wsbm.1539] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 09/18/2021] [Accepted: 09/22/2021] [Indexed: 12/24/2022]
Abstract
Human papillomaviruses (HPVs) are the etiological agent of a significant, and increasing, fraction of head and neck squamous cell carcinomas (HNSCC)-a heterogenous group of malignancies in the head and neck region. HPV infection accounts for approximately 25% of all cases, with the remainder typically caused by smoking and excessive alcohol consumption. These distinct etiologies lead to profound clinical and immunological differences between HPV-positive (HPV+ ) and HPV-negative (HPV- ) HNSCC, likely related to the expression of exogenous viral antigens in the HPV+ subtype. Specifically, HPV+ HNSCC patients generally exhibit better treatment response compared to those with HPV- disease, leading to a more favorable prognosis, with lower recurrence rate, and longer overall survival time. Importantly, a plethora of studies have illustrated that the tumor immune microenvironment (TIME) of HPV+ HNSCC has a strikingly distinct immune composition to that of its HPV- counterpart. The HPV+ TIME is characterized as being immunologically "hot," with more immune infiltration, higher levels of T-cell activation, and higher levels of immunoregulation compared to the more immunologically "cold" HPV- TIME. In general, cancers with an immune "hot" TIME exhibit better treatment response and superior clinical outcomes in comparison to their immune "cold" counterparts. Indeed, this phenomenon has also been observed in HPV+ HNSCC patients, highlighting the critical role of the TIME in influencing prognosis, and further validating the use of cancer therapies that capitalize on the mobilization and/or modulation of the TIME. This article is categorized under: Cancer > Molecular and Cellular Physiology Infectious Diseases > Molecular and Cellular Physiology.
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Affiliation(s)
- Steven F Gameiro
- Department of Microbiology and Immunology, The University of Western Ontario, London, Ontario, Canada
| | - Andris M Evans
- Department of Microbiology and Immunology, The University of Western Ontario, London, Ontario, Canada
| | - Joe S Mymryk
- Department of Microbiology and Immunology, The University of Western Ontario, London, Ontario, Canada.,Department of Otolaryngology, The University of Western Ontario, London, Ontario, Canada.,Department of Oncology, The University of Western Ontario, London, Ontario, Canada.,London Regional Cancer Program, Lawson Health Research Institute, London, Ontario, Canada
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EVs delivery of miR-1915-3p improves the chemotherapeutic efficacy of oxaliplatin in colorectal cancer. Cancer Chemother Pharmacol 2021; 88:1021-1031. [PMID: 34599680 DOI: 10.1007/s00280-021-04348-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 05/30/2021] [Indexed: 02/06/2023]
Abstract
PURPOSE Oxaliplatin is a crucial component of the combinatorial chemotherapeutic standard of care for advanced colorectal cancer (CRC). Unfortunately, a serious barrier to effective oxaliplatin treatment is drug resistance due to epithelial-mesenchymal transitioning (EMT). Interestingly, stable oxaliplatin-resistant CRC cell lines show differential expression of miR-1915-3p; thus, this microRNA may represent a potential modifier of oxaliplatin resistance in CRC cells. METHODS miR-1915-3p was over-expressed in oxaliplatin-resistant CRC cells and a non-tumorigenic intestinal cell line (FHC) via lentiviral transduction. Extracellular vesicles (EVs) were purified from transduced FHC cells and co-incubated with CRC cells. Expression levels of miR-1915-3p and other RNA species were assessed by RT-qPCR, while protein expression levels were assessed by Western blotting. The effects of miR-1915-3p on CRC viability were evaluated by proliferation, apoptosis assays, and Transwell assays. Effects of miR-1915-3p over-expression on in vivo oxaliplatin sensitivity was tested via murine xenograft models. RESULTS miRNA-1915-3p decreased EMT marker expression in oxaliplatin-resistant CRC cell lines and in vivo. FHC cells were able to produce and secrete miR-1915-3p-containing EVs, which we employed to mediate miR-1915-3p delivery to oxaliplatin-resistant CRC cells and increase their oxaliplatin sensitivity in vivo and in vitro. Mechanistically, miR-1915-3p overexpression downregulated the EMT-promoting oncogenes 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) and ubiquitin carboxyl-terminal hydrolase 2 (USP2) as well as upregulated E-cadherin (a cell adhesion mediator). miR-1915-3p's effects on chemosensitivity and EMT were mediated by its regulation of PFKFB3 and USP2. CONCLUSION Exosomal delivery of miR-1915-3p can improve the chemotherapeutic efficacy of oxaliplatin in CRC cells by suppressing the EMT-promoting oncogenes PFKFB3 and USP2.
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Choi B, Kim DH. Multifunctional Nanocarriers-Mediated Synergistic Combination of Immune Checkpoint Inhibitor Cancer Immunotherapy and Interventional Oncology Therapy. ADVANCED NANOBIOMED RESEARCH 2021; 1:2100010. [PMID: 35663354 PMCID: PMC9162439 DOI: 10.1002/anbr.202100010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Immune checkpoint inhibitor (ICI) cancer immunotherapies are becoming one of the standard therapies for cancer patients. However, ICI cancer immunotherapy's overall response rate is still moderate and even combinational ICI cancer immunotherapies are not showing significant improvement in therapeutic outcomes. Only a subset of patients responds to the therapy due to the resistance and ignorance to the ICI cancer immunotherapy. Following immune-related adverse events (irAEs) are also limiting the whole therapeutic regimens. New approaches that can increase the immunotherapeutic efficacy and reduce systemic irAEs are required. Recently, multifunctional nanocarriers, which can extend the half-life of ICIs and modulate tumor microenvironment (TME), have shown a substantial opportunity to enhance ICI cancer immunotherapies. Interventional oncology (IO) allowing simultaneous diagnosis, immunogenic loco-regional therapeutic delivery, and real-time monitoring of the treatment efficacy have advanced to demonstrate the effective conversion of TME. The use of multifunctional nanocarriers with the IO therapies amplify the image guidance capability and immunogenic therapeutic localization for the potential combinational ICI cancer immunotherapy. This article will discuss the emerging opportunity of multifunctional nanocarriers mediated synergistic combination of ICI cancer immunotherapy and IO local therapy.
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Affiliation(s)
- Bongseo Choi
- Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Dong-Hyun Kim
- Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
- Department of Biomedical Engineering, McCormick School of Engineering, Evanston, IL 60208, USA
- Robert H. Lurie Comprehensive Cancer Center, Chicago, IL 60611, USA
- Department of Bioengineering, University of Illinois at Chicago, Chicago, IL 60607, USA
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47
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Cui W, Popat S. Immune Checkpoint Inhibition for Unresectable Malignant Pleural Mesothelioma. Drugs 2021; 81:971-984. [PMID: 34106454 DOI: 10.1007/s40265-021-01506-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/17/2021] [Indexed: 12/29/2022]
Abstract
Immune checkpoint inhibitors (ICI) have shown important but variable efficacy in mesothelioma despite a lack of strong biological rationale. Initial trials assessed ICI monotherapy in patients with relapsed mesothelioma, with objective response rates (ORR) between 4.5 and 29%, median progression-free survival (PFS) between 2.5-6.2 months, and median overall survival (OS) between 7.7 and 18.0 months. In randomised trials of chemotherapy pre-treated patients, nivolumab was recently shown to improve PFS compared to placebo, but tremelimumab was not superior to placebo, and there was no difference in OS between pembrolizumab and chemotherapy. However, response to combination ICI appear more promising in both pre-treated and treatment-naïve mesothelioma. The randomised Phase 3 trial of upfront ipilimumab-nivolumab versus platinum-pemetrexed chemotherapy demonstrated improved OS favouring ipilimumab-nivolumab (HR 0.74, 96.6% CI 0.60-0.91; p = 0.0020), establishing this regimen as a new standard of care, especially in non-epithelioid histological subtypes. However, initially PFS was poorer in the ipilimumab-nivolumab than chemotherapy treatment arms. A single-arm Phase 2 trial of upfront platinum chemotherapy and durvalumab met its primary endpoint, with a 6-month PFS of 57% (95% CI 44-70) with chemo-immunotherapy under evaluation as an alternative upfront regimen. Several questions remain unanswered. Comparative studies of chemo-immunotherapy versus chemotherapy are underway, but these do not compare chemo-immunotherapy to combination ICI. There is a critical need to establish predictive biomarkers to improve patient selection. As ICI use moves into the front-line setting, patient selection, role for operable patients, and understanding ICI resistance mechanisms alongside role of ICI rechallenge in previous responders need further evaluation.
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Affiliation(s)
- Wanyuan Cui
- Lung Unit, Department of Medicine, Royal Marsden NHS Foundation Trust, London, SW3 6JJ, UK
| | - Sanjay Popat
- Lung Unit, Department of Medicine, Royal Marsden NHS Foundation Trust, London, SW3 6JJ, UK. .,National Heart and Lung Institute, Imperial College London, London, UK. .,Thoracic Oncology, Institute of Cancer Research, London, UK.
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48
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Zalfa C, Paust S. Natural Killer Cell Interactions With Myeloid Derived Suppressor Cells in the Tumor Microenvironment and Implications for Cancer Immunotherapy. Front Immunol 2021; 12:633205. [PMID: 34025641 PMCID: PMC8133367 DOI: 10.3389/fimmu.2021.633205] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 02/12/2021] [Indexed: 12/17/2022] Open
Abstract
The tumor microenvironment (TME) is a complex and heterogeneous environment composed of cancer cells, tumor stroma, a mixture of tissue-resident and infiltrating immune cells, secreted factors, and extracellular matrix proteins. Natural killer (NK) cells play a vital role in fighting tumors, but chronic stimulation and immunosuppression in the TME lead to NK cell exhaustion and limited antitumor functions. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of myeloid cells with potent immunosuppressive activity that gradually accumulate in tumor tissues. MDSCs interact with innate and adaptive immune cells and play a crucial role in negatively regulating the immune response to tumors. This review discusses MDSC-mediated NK cell regulation within the TME, focusing on critical cellular and molecular interactions. We review current strategies that target MDSC-mediated immunosuppression to enhance NK cell cytotoxic antitumor activity. We also speculate on how NK cell-based antitumor immunotherapy could be improved.
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Affiliation(s)
| | - Silke Paust
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, United States
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49
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Khojah R, Xiao Z, Panduranga MK, Bogumil M, Wang Y, Goiriena-Goikoetxea M, Chopdekar RV, Bokor J, Carman GP, Candler RN, Di Carlo D. Single-Domain Multiferroic Array-Addressable Terfenol-D (SMArT) Micromagnets for Programmable Single-Cell Capture and Release. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2021; 33:e2006651. [PMID: 33831219 DOI: 10.1002/adma.202006651] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 01/14/2021] [Indexed: 06/12/2023]
Abstract
Programming magnetic fields with microscale control can enable automation at the scale of single cells ≈10 µm. Most magnetic materials provide a consistent magnetic field over time but the direction or field strength at the microscale is not easily modulated. However, magnetostrictive materials, when coupled with ferroelectric material (i.e., strain-mediated multiferroics), can undergo magnetization reorientation due to voltage-induced strain, promising refined control of magnetization at the micrometer-scale. This work demonstrates the largest single-domain microstructures (20 µm) of Terfenol-D (Tb0.3 Dy0.7 Fe1.92 ), a material that has the highest magnetostrictive strain of any known soft magnetoelastic material. These Terfenol-D microstructures enable controlled localization of magnetic beads with sub-micrometer precision. Magnetically labeled cells are captured by the field gradients generated from the single-domain microstructures without an external magnetic field. The magnetic state on these microstructures is switched through voltage-induced strain, as a result of the strain-mediated converse magnetoelectric effect, to release individual cells using a multiferroic approach. These electronically addressable micromagnets pave the way for parallelized multiferroics-based single-cell sorting under digital control for biotechnology applications.
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Affiliation(s)
- Reem Khojah
- Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | - Zhuyun Xiao
- Department of Electrical and Computer Engineering, University of California, Los Angeles, Los Angeles, CA, 90095-1594, USA
| | - Mohanchandra K Panduranga
- Department of Mechanical and Aerospace Engineering, University of California, Los Angeles, Los Angeles, CA, 90095-1597, USA
| | - Michael Bogumil
- Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | - Yilian Wang
- Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | - Maite Goiriena-Goikoetxea
- Department of Electrical Engineering and Computer Science, University of California, Berkeley, Berkeley, CA, 94720-1770, USA
- Department of Electricity and Electronics, University of the Basque Country (UPV/EHU), Leioa, 48940, Spain
| | - Rajesh V Chopdekar
- Advanced Light Source, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA
| | - Jeffrey Bokor
- Department of Electrical Engineering and Computer Science, University of California, Berkeley, Berkeley, CA, 94720-1770, USA
| | - Gregory P Carman
- Department of Mechanical and Aerospace Engineering, University of California, Los Angeles, Los Angeles, CA, 90095-1597, USA
| | - Rob N Candler
- Department of Electrical and Computer Engineering, University of California, Los Angeles, Los Angeles, CA, 90095-1594, USA
- Department of Mechanical and Aerospace Engineering, University of California, Los Angeles, Los Angeles, CA, 90095-1597, USA
- California NanoSystems Institute, Los Angeles, CA, 90095, USA
| | - Dino Di Carlo
- Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, 90095, USA
- Department of Mechanical and Aerospace Engineering, University of California, Los Angeles, Los Angeles, CA, 90095-1597, USA
- California NanoSystems Institute, Los Angeles, CA, 90095, USA
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Ruotsalainen J, Lopez‐Ramos D, Rogava M, Shridhar N, Glodde N, Gaffal E, Hölzel M, Bald T, Tüting T. The myeloid cell type I IFN system promotes antitumor immunity over pro-tumoral inflammation in cancer T-cell therapy. Clin Transl Immunology 2021; 10:e1276. [PMID: 33968406 PMCID: PMC8082713 DOI: 10.1002/cti2.1276] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Revised: 08/24/2020] [Accepted: 03/25/2021] [Indexed: 11/11/2022] Open
Abstract
OBJECTIVES Type I interferons are evolutionally conserved cytokines, with broad antimicrobial and immunoregulatory functions. Despite well-characterised role in spontaneous cancer immunosurveillance, the function of type I IFNs in cancer immunotherapy remains incompletely understood. METHODS We utilised genetic mouse models to explore the role of the type I IFN system in CD8+ T-cell immunotherapy targeting the melanocytic lineage antigen gp100. RESULTS The therapeutic efficacy of adoptively transferred T cells was found to depend on a functional type I IFN system in myeloid immune cells. Compromised type I IFN signalling in myeloid immune cells did not prevent expansion, tumor infiltration or effector function of melanoma-specific Pmel-1 CD8+ T cells. However, melanomas growing in globally (Ifnar1-/-) or conditionally (Ifnar1ΔLysM) type I IFN system-deficient mice displayed increased myeloid infiltration, hypoxia and melanoma cell dedifferentiation. Mechanistically, hypoxia was found to induce dedifferentiation and loss of the gp100 target antigen in melanoma cells and type I IFN could directly inhibit the inflammatory activation of myeloid cells. Unexpectedly, the immunotherapy induced significant reduction in tumor blood vessel density and whereas host type I IFN system was not required for the vasculosculpting, it promoted vessel permeability. CONCLUSION Our results substantiate a complex and plastic phenotypic interconnection between melanoma and myeloid cells in the context of T-cell immunotherapy. Type I IFN signalling in myeloid cells was identified as a key regulator of the balance between antitumor immunity and disease-promoting inflammation, thus supporting the development of novel combinatorial immunotherapies targeting this immune cell compartment.
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Affiliation(s)
- Janne Ruotsalainen
- Laboratory of Experimental DermatologyDepartment of DermatologyUniversity Hospital MagdeburgMagdeburgGermany
| | - Dorys Lopez‐Ramos
- Laboratory of Experimental DermatologyDepartment of DermatologyUniversity Hospital MagdeburgMagdeburgGermany
| | - Meri Rogava
- Laboratory of Experimental DermatologyDepartment of DermatologyUniversity Hospital MagdeburgMagdeburgGermany
| | - Naveen Shridhar
- Laboratory of Experimental DermatologyDepartment of DermatologyUniversity Hospital MagdeburgMagdeburgGermany
| | - Nicole Glodde
- Laboratory of Experimental DermatologyDepartment of DermatologyUniversity Hospital MagdeburgMagdeburgGermany
- Institute of Experimental Oncology (IEO)Medical FacultyUniversity Hospital BonnUniversity of BonnBonnGermany
| | - Evelyn Gaffal
- Laboratory of Experimental DermatologyDepartment of DermatologyUniversity Hospital MagdeburgMagdeburgGermany
| | - Michael Hölzel
- Institute of Experimental Oncology (IEO)Medical FacultyUniversity Hospital BonnUniversity of BonnBonnGermany
| | - Tobias Bald
- Laboratory of Experimental DermatologyDepartment of DermatologyUniversity Hospital MagdeburgMagdeburgGermany
- Laboratory of Tumor‐ImmunobiologyInstitute of Experimental Oncology (IEO)Medical FacultyUniversity Hospital BonnUniversity of BonnBonnGermany
| | - Thomas Tüting
- Laboratory of Experimental DermatologyDepartment of DermatologyUniversity Hospital MagdeburgMagdeburgGermany
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