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Haddadin L, Sun X. Stem Cells in Cancer: From Mechanisms to Therapeutic Strategies. Cells 2025; 14:538. [PMID: 40214491 PMCID: PMC11988674 DOI: 10.3390/cells14070538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2025] [Revised: 03/23/2025] [Accepted: 04/01/2025] [Indexed: 04/14/2025] Open
Abstract
Stem cells have emerged as a pivotal area of research in the field of oncology, offering new insights into the mechanisms of cancer initiation, progression, and resistance to therapy. This review provides a comprehensive overview of the role of stem cells in cancer, focusing on cancer stem cells (CSCs), their characteristics, and their implications for cancer therapy. We discuss the origin and identification of CSCs, their role in tumorigenesis, metastasis, and drug resistance, and the potential therapeutic strategies targeting CSCs. Additionally, we explore the use of normal stem cells in cancer therapy, focusing on their role in tissue regeneration and their use as delivery vehicles for anticancer agents. Finally, we highlight the challenges and future directions in stem cell research in cancer.
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Affiliation(s)
| | - Xueqin Sun
- Cancer Genome and Epigenetics Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
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2
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Melemenidis S, Viswanathan V, Dutt S, Kapadia N, Lau B, Soto LA, Ashraf MR, Thakur B, Mutahar AZI, Skinner LB, Yu AS, Surucu M, Casey KM, Rankin EB, Horst KC, Graves EE, Loo BW, Dirbas FM. Effectiveness of FLASH vs. Conventional Dose Rate Radiotherapy in a Model of Orthotopic, Murine Breast Cancer. Cancers (Basel) 2025; 17:1095. [PMID: 40227580 PMCID: PMC11988084 DOI: 10.3390/cancers17071095] [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: 02/05/2025] [Revised: 03/15/2025] [Accepted: 03/17/2025] [Indexed: 04/15/2025] Open
Abstract
Introduction: Radiotherapy is effective for breast cancer treatment but often causes undesirable side effects that impair quality of life. Ultra-high dose rate radiotherapy (FLASH) has shown reduced normal tissue toxicity while achieving comparable tumor growth delay compared to conventional dose rate radiotherapy (CONV). This study evaluated whether FLASH could achieve similar tumor control as CONV with tumor eradication as the primary endpoint, in an orthotopic breast cancer model. Methods: Non-metastatic, orthotopic tumors were generated in the left fourth mammary fat pad using the Py117 mammary tumor cell line in syngeneic C57BL/6J mice. Two sequential irradiation studies were performed using FLASH (93-200 Gy/s) and CONV (0.08 Gy/s) electron beams. Single fractions of 20, 25, or 30 Gy were applied to tumors with varying abdominal wall treatment fields (~3.75 or 2.5 mm treatment margin to tumor). Results: Both FLASH and CONV demonstrated comparable efficacy. Small tumors treated with 30 Gy and larger abdominal wall treatment fields appeared to have complete eradication at 30 days but also exhibited the highest skin toxicity, limiting follow-up and preventing confirmation of eradication. Smaller abdominal wall treatment fields reduced skin toxicity and allowed for extended follow-up, which resulted in 75% tumor-free survival at 48 days. Larger tumors showed growth delay but no eradication. Conclusions: In this preclinical, non-metastatic orthotopic breast cancer model, FLASH and CONV demonstrated equivalent tumor control with single-fraction doses of 20, 25, or 30 Gy. Overall, 30 Gy achieved the highest eradication rate but also resulted in the most pronounced skin toxicity.
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Affiliation(s)
- Stavros Melemenidis
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA; (S.M.); (V.V.); (S.D.); (B.L.); (L.A.S.); (M.R.A.); (L.B.S.); (A.S.Y.); (M.S.); (E.B.R.); (K.C.H.); (E.E.G.); (B.W.L.J.)
| | - Vignesh Viswanathan
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA; (S.M.); (V.V.); (S.D.); (B.L.); (L.A.S.); (M.R.A.); (L.B.S.); (A.S.Y.); (M.S.); (E.B.R.); (K.C.H.); (E.E.G.); (B.W.L.J.)
| | - Suparna Dutt
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA; (S.M.); (V.V.); (S.D.); (B.L.); (L.A.S.); (M.R.A.); (L.B.S.); (A.S.Y.); (M.S.); (E.B.R.); (K.C.H.); (E.E.G.); (B.W.L.J.)
| | - Naviya Kapadia
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA; (S.M.); (V.V.); (S.D.); (B.L.); (L.A.S.); (M.R.A.); (L.B.S.); (A.S.Y.); (M.S.); (E.B.R.); (K.C.H.); (E.E.G.); (B.W.L.J.)
| | - Brianna Lau
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA; (S.M.); (V.V.); (S.D.); (B.L.); (L.A.S.); (M.R.A.); (L.B.S.); (A.S.Y.); (M.S.); (E.B.R.); (K.C.H.); (E.E.G.); (B.W.L.J.)
| | - Luis A. Soto
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA; (S.M.); (V.V.); (S.D.); (B.L.); (L.A.S.); (M.R.A.); (L.B.S.); (A.S.Y.); (M.S.); (E.B.R.); (K.C.H.); (E.E.G.); (B.W.L.J.)
| | - M. Ramish Ashraf
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA; (S.M.); (V.V.); (S.D.); (B.L.); (L.A.S.); (M.R.A.); (L.B.S.); (A.S.Y.); (M.S.); (E.B.R.); (K.C.H.); (E.E.G.); (B.W.L.J.)
| | - Banita Thakur
- Department of Surgery, Stanford University School of Medicine, Stanford Cancer Institute, Stanford, CA 94305, USA; (B.T.); (A.Z.I.M.)
| | - Adel Z. I. Mutahar
- Department of Surgery, Stanford University School of Medicine, Stanford Cancer Institute, Stanford, CA 94305, USA; (B.T.); (A.Z.I.M.)
| | - Lawrie B. Skinner
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA; (S.M.); (V.V.); (S.D.); (B.L.); (L.A.S.); (M.R.A.); (L.B.S.); (A.S.Y.); (M.S.); (E.B.R.); (K.C.H.); (E.E.G.); (B.W.L.J.)
| | - Amy S. Yu
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA; (S.M.); (V.V.); (S.D.); (B.L.); (L.A.S.); (M.R.A.); (L.B.S.); (A.S.Y.); (M.S.); (E.B.R.); (K.C.H.); (E.E.G.); (B.W.L.J.)
| | - Murat Surucu
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA; (S.M.); (V.V.); (S.D.); (B.L.); (L.A.S.); (M.R.A.); (L.B.S.); (A.S.Y.); (M.S.); (E.B.R.); (K.C.H.); (E.E.G.); (B.W.L.J.)
| | - Kerriann M. Casey
- Department of Comparative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA;
| | - Erinn B. Rankin
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA; (S.M.); (V.V.); (S.D.); (B.L.); (L.A.S.); (M.R.A.); (L.B.S.); (A.S.Y.); (M.S.); (E.B.R.); (K.C.H.); (E.E.G.); (B.W.L.J.)
| | - Kathleen C. Horst
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA; (S.M.); (V.V.); (S.D.); (B.L.); (L.A.S.); (M.R.A.); (L.B.S.); (A.S.Y.); (M.S.); (E.B.R.); (K.C.H.); (E.E.G.); (B.W.L.J.)
| | - Edward E. Graves
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA; (S.M.); (V.V.); (S.D.); (B.L.); (L.A.S.); (M.R.A.); (L.B.S.); (A.S.Y.); (M.S.); (E.B.R.); (K.C.H.); (E.E.G.); (B.W.L.J.)
| | - Billy W. Loo
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA; (S.M.); (V.V.); (S.D.); (B.L.); (L.A.S.); (M.R.A.); (L.B.S.); (A.S.Y.); (M.S.); (E.B.R.); (K.C.H.); (E.E.G.); (B.W.L.J.)
| | - Frederick M. Dirbas
- Department of Surgery, Stanford University School of Medicine, Stanford Cancer Institute, Stanford, CA 94305, USA; (B.T.); (A.Z.I.M.)
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Quan T, Li R, Gao T. The Intestinal Macrophage-Intestinal Stem Cell Axis in Inflammatory Bowel Diseases: From Pathogenesis to Therapy. Int J Mol Sci 2025; 26:2855. [PMID: 40243444 PMCID: PMC11988290 DOI: 10.3390/ijms26072855] [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: 02/19/2025] [Revised: 03/19/2025] [Accepted: 03/19/2025] [Indexed: 04/18/2025] Open
Abstract
The gut plays a crucial role in digestion and immunity, so its balance is essential to overall health. This balance relies on dynamic interactions between intestinal epithelial cells, immune cells, and crypt stem cells. Inflammatory bowel disease (IBD), which consists of ulcerative colitis and Crohn's disease, is a chronic relapsing inflammatory disease of the gastrointestinal tract closely related to immune dysfunction. Stem cells, known for their ability to self-renew and differentiate, play an important role in repairing damaged intestinal epithelium and maintaining homeostasis in vivo. Macrophages are key gatekeepers of intestinal immune homeostasis and have a significant impact on IBD. Current research has focused on the link between epithelial cells and stem cells, but interactions with macrophages, which have been recognized as attractive targets for the development of new therapeutic approaches to disease, have been less explored. Recently, the developing field of immunometabolism has reinforced that metabolic reprogramming is a key determinant of macrophage function and subsequent disease progression. The aim of this review is to explore the role of the macrophage-stem cell axis in the maintenance of intestinal homeostasis and to summarize potential approaches to treating IBD by manipulating the cellular metabolism of macrophages, as well as the main opportunities and challenges faced. In summary, our overview provides a framework for understanding the critical role of macrophage immunometabolism in maintaining gut health and potential therapeutic targets.
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Affiliation(s)
| | | | - Ting Gao
- College of Veterinary Medicine, China Agricultural University, Beijing 100083, China; (T.Q.); (R.L.)
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Tian J, Li Y, Tong Y, Zhang Y, Zhao T, Kang Y, Bi Q. Uridine-cytidine kinase 2 is correlated with immune, DNA damage repair and promotion of cancer stemness in pan-cancer. Front Oncol 2025; 15:1503300. [PMID: 39931080 PMCID: PMC11807824 DOI: 10.3389/fonc.2025.1503300] [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: 09/28/2024] [Accepted: 01/03/2025] [Indexed: 02/13/2025] Open
Abstract
Background UCK2 (Uridine-Cytidine Kinase 2) is a promising prognostic marker for malignant tumors, but its association with immune infiltration and cancer stemness in pan-cancer remains to be fully understood. we find that gene UCK2 is closed related to RNA stemness scores (RNAss) and DNA stemness scores (DNAss), which is measured the tumor stemness. We also discover an association between UCK2 expression and immune cells by CIBERSORT algorithm, ESTIMATE algorithm and ssGSEA algorithm, especially, related to T cell, monocytes, mast cells, and macrophages. This study aims to shed light on the role and possible mechanism of UCK2 in pan-cancer. Methods We used the R programming language for pan-cancer bulk sequencing data analysis, which were obtained from the University of California, Santa Cruz (UCSC) datasets. UCSC database is a very useful for explore data from TCGA and other cancer genomics datasets, The data we explored at the UCK2 transcriptome level came from TCGA data in the UCSC database. We explored differential UCK2 expression between tumor and normal samples. Immunohistochemistry (IHC) was utilized to validate the expression of UCK2 in different types cancers using tumor tissue chips. The correlations of UCK2 with prognosis, genetic instability, DNA repair, cancer stem cell characteristics, and immune cell infiltration were investigated. Furthermore, single-cell datasets, acquired from the Gene Expression Omnibus (GEO) database, were used to validate the relationship between UCK2 and immune cells. GEO is a famous public genomics database supporting freely disseminates microarray data. Finally, we analyzed the correlation between UCK2 and drug sensitivity. Results UCK2 expression was observed to be high in most cancers and was remarkably related to the prognosis of pan-cancers. We found that the increased UCK2 expression was associated with higher genetic instability. Additionally, positive relationships were observed between UCK2 expression and mismatch repair genes, homologous recombination repair genes, and cancer stemness across different cancer types. There were significant correlations between UCK2 and T cells, monocytes, mast cells, and macrophages. Moreover, as expected, the immune checkpoint human leucocyte antigen (HLA) was found to be negatively related to UCK2. Similarly, UCK2 was also observed to have a negative association with major histocompatibility complex (MHC) genes. We noted that UCK2 had significant correlations with the sensitivity to various anti-cancer drug. Conclusion We have observed that UCK2 plays pivotal roles in prognosis and tumor immunity, and it is associated with DNA repair and cancer stemness. The UCK2 gene exhibits a strong correlation with the immune checkpoints HLA. This study highlights its potential impact on drug sensitivity.
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Affiliation(s)
- Jinlong Tian
- Graduate School of Bengbu Medical University, Bengbu, Anhui, China
| | - Yanlei Li
- Graduate School of Bengbu Medical University, Bengbu, Anhui, China
| | - Yu Tong
- Sports Medicine Center, Department of Orthopedics, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
| | - Yuan Zhang
- Department of Rheumatology and Immunology, The Second Affiliated Hospital of Zhejiang University of Traditional Chinese Medicine, Hangzhou, China
| | - Tingxiao Zhao
- Sports Medicine Center, Department of Orthopedics, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
| | - Yao Kang
- Sports Medicine Center, Department of Orthopedics, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
| | - Qing Bi
- Graduate School of Bengbu Medical University, Bengbu, Anhui, China
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Mills M, Emori C, Kumar P, Boucher Z, George J, Bolcun-Filas E. Single-cell and bulk transcriptional profiling of mouse ovaries reveals novel genes and pathways associated with DNA damage response in oocytes. Dev Biol 2025; 517:55-72. [PMID: 39306223 DOI: 10.1016/j.ydbio.2024.09.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 09/11/2024] [Accepted: 09/16/2024] [Indexed: 09/25/2024]
Abstract
Immature oocytes enclosed in primordial follicles stored in female ovaries are under constant threat of DNA damage induced by endogenous and exogenous factors. Checkpoint kinase 2 (CHEK2) is a key mediator of the DNA damage response (DDR) in all cells. Genetic studies have shown that CHEK2 and its downstream targets, p53, and TAp63, regulate primordial follicle elimination in response to DNA damage. However, the mechanism leading to their demise is still poorly characterized. Single-cell and bulk RNA sequencing were used to determine the DDR in wild-type and Chek2-deficient ovaries. A low but oocyte-lethal dose of ionizing radiation induces ovarian DDR that is solely dependent on CHEK2. DNA damage activates multiple response pathways related to apoptosis, p53, interferon signaling, inflammation, cell adhesion, and intercellular communication. These pathways are differentially employed by different ovarian cell types, with oocytes disproportionately affected by radiation. Novel genes and pathways are induced by radiation specifically in oocytes, shedding light on their sensitivity to DNA damage, and implicating a coordinated response between oocytes and pregranulosa cells within the follicle. These findings provide a foundation for future studies on the specific mechanisms regulating oocyte survival in the context of aging, therapeutic and environmental genotoxic exposures.
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Affiliation(s)
- Monique Mills
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA; The Graduate School of Biomedical Science and Engineering, University of Maine, Orono, ME, 04469, USA
| | - Chihiro Emori
- Department of Experimental Genome Research, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, 5650871, Japan
| | - Parveen Kumar
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06110, USA
| | - Zachary Boucher
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA
| | - Joshy George
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06110, USA
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Jiang X, Yang M, Zhang W, Shi D, Li Y, He L, Huang S, Chen B, Chen X, Kong L, Pan Y, Deng P, Wang R, Ouyang Y, Chen X, Li J, Li Z, Zou H, Zhang Y, Song L. Targeting the SPC25/RIOK1/MYH9 Axis to Overcome Tumor Stemness and Platinum Resistance in Epithelial Ovarian Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2406688. [PMID: 39488790 DOI: 10.1002/advs.202406688] [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: 06/17/2024] [Revised: 09/29/2024] [Indexed: 11/04/2024]
Abstract
In epithelial ovarian cancer (EOC), platinum resistance, potentially mediated by cancer stem cells (CSCs), often leads to relapse and treatment failure. Here, the role of spindle pole body component 25 (SPC25) as a key determinant promoting stemness and platinum resistance in EOC cells, with its expression being correlated with adverse clinical outcomes is delineated. Mechanistically, SPC25 acts as a scaffolding platform, orchestrating the assembly of an SPC25/RIOK1/MYH9 trimeric complex, triggering RIOK1-mediated phosphorylation of MYH9 at Ser1943. This prompts MYH9 to disengage from the cytoskeleton, augmenting its nuclear accumulation, thus potentiating CTNNB1 transcription and subsequent activation of Wnt/β-catenin signaling. CBP1, a competitive inhibitory peptide, can disrupt the formation of the aforementioned trimeric complex, diminishing the activity of the SPC25/RIOK1/MYH9 axis-mediated Wnt/β-catenin signaling, and thus attenuate CSC phenotypes, thereby enhancing platinum efficacy in vitro, in vivo, and in patient-derived organoids. Therefore, targeting the SPC25/RIOK1/MYH9 axis, which mediates the maintenance of stemness and platinum resistance in EOC cells, may enhance platinum sensitivity and increase survival in patients with EOC.
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Affiliation(s)
- Xingyu Jiang
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China
| | - Muwen Yang
- Department of Radiation Oncology, Shenzhen Key Laboratory of Gastrointestinal Cancer Translational Research, Peking University Shenzhen Hospital, Shenzhen, Guangdong, 518036, China
| | - Weijing Zhang
- Department of Radiology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China
| | - Dongni Shi
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China
| | - Yue Li
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China
| | - Lixin He
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China
| | - Shumei Huang
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510060, China
| | - Boyu Chen
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China
| | - Xuwei Chen
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China
| | - Lingzhi Kong
- Department of Pathology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China
| | - Yibing Pan
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China
| | - Pinwei Deng
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China
| | - Rui Wang
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China
| | - Ying Ouyang
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China
| | - Xiangfu Chen
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China
| | - Jun Li
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510060, China
| | - Zheng Li
- Department of Gynecologic Oncology, The Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital), Kunming, Yunnan, 650118, China
| | - Hequn Zou
- School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, China
| | - Yanna Zhang
- Department of Gynecology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China
| | - Libing Song
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China
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Chen R, Liu Y, Xie J. Construction of a pathomics model for predicting mRNAsi in lung adenocarcinoma and exploration of biological mechanism. Heliyon 2024; 10:e37100. [PMID: 39286147 PMCID: PMC11402732 DOI: 10.1016/j.heliyon.2024.e37100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 08/04/2024] [Accepted: 08/27/2024] [Indexed: 09/19/2024] Open
Abstract
Objective This study aimed to predict the level of stemness index (mRNAsi) and survival prognosis of lung adenocarcinoma (LUAD) using pathomics model. Methods From The Cancer Genome Atlas (TCGA) database, 327 LUAD patients were randomly assigned to a training set (n = 229) and a validation set (n = 98) for pathomics model development and evaluation. PyRadiomics was used to extract pathomics features, followed by feature selection using the mRMR-RFE algorithm. In the training set, Gradient Boosting Machine (GBM) was utilized to establish a model for predicting mRNAsi in LUAD. The model's predictive performance was evaluated using ROC curves, calibration curves, and decision curve analysis (DCA). Prognostic analysis was conducted using Kaplan-Meier curves and cox regression. Additionally, gene enrichment analysis, tumor microenvironment analysis, and tumor mutational burden (TMB) analysis were performed to explore the biological mechanisms underlying the pathomics prediction model. Results Multivariable cox analysis (HR = 1.488, 95 % CI 1.012-2.187, P = 0.043) identified mRNAsi as a prognostic risk factor for LUAD. A total of 465 pathomics features were extracted from TCGA-LUAD histopathological images, and ultimately, the most representative 8 features were selected to construct the predictive model. ROC curves demonstrated the significant predictive value of the model for mRNAsi in both the training set (AUC = 0.769) and the validation set (AUC = 0.757). Calibration curves and Hosmer-Lemeshow goodness-of-fit test showed good consistency between the model's prediction of mRNAsi levels and the actual values. DCA indicated a good net benefit of the model. The prediction of mRNAsi levels by the pathomics model is represented using the pathomics score (PS). PS was strongly associated with the prognosis of LUAD (HR = 1.496, 95 % CI 1.008-2.222, P = 0.046). Signaling pathways related to DNA replication and damage repair were significantly enriched in the high PS group. Prediction of immune therapy response indicated significantly reduced Dysfunction in the high PS group (P < 0.001). The high PS group exhibited higher TMB values (P < 0.001). Conclusions The predictive model constructed based on pathomics features can forecast the mRNAsi and survival risk of LUAD. This model holds promise to aid clinical practitioners in identifying high-risk patients and devising more optimized treatment plans for patients by jointly employing therapeutic strategies targeting cancer stem cells (CSCs).
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Affiliation(s)
- Rui Chen
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, No.1, Minde Road, Donghu District, Nanchang, Jiangxi, 330006, China
| | - Yuzhen Liu
- Department of Oncology, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, China
| | - Junping Xie
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, No.1, Minde Road, Donghu District, Nanchang, Jiangxi, 330006, China
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8
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Eminaga O, Lau H, Shkolyar E, Wardelmann E, Abbas M. Deep learning identifies histopathologic changes in bladder cancers associated with smoke exposure status. PLoS One 2024; 19:e0305135. [PMID: 39083547 PMCID: PMC11290674 DOI: 10.1371/journal.pone.0305135] [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: 02/10/2023] [Accepted: 05/23/2024] [Indexed: 08/02/2024] Open
Abstract
Smoke exposure is associated with bladder cancer (BC). However, little is known about whether the histologic changes of BC can predict the status of smoke exposure. Given this knowledge gap, the current study investigated the potential association between histology images and smoke exposure status. A total of 483 whole-slide histology images of 285 unique cases of BC were available from multiple centers for BC diagnosis. A deep learning model was developed to predict the smoke exposure status and externally validated on BC cases. The development set consisted of 66 cases from two centers. The external validation consisted of 94 cases from remaining centers for patients who either never smoked cigarettes or were active smokers at the time of diagnosis. The threshold for binary categorization was fixed to the median confidence score (65) of the development set. On external validation, AUC was used to assess the randomness of predicted smoke status; we utilized latent feature presentation to determine common histologic patterns for smoke exposure status and mixed effect logistic regression models determined the parameter independence from BC grade, gender, time to diagnosis, and age at diagnosis. We used 2,000-times bootstrap resampling to estimate the 95% Confidence Interval (CI) on the external validation set. The results showed an AUC of 0.67 (95% CI: 0.58-0.76), indicating non-randomness of model classification, with a specificity of 51.2% and sensitivity of 82.2%. Multivariate analyses revealed that our model provided an independent predictor for smoke exposure status derived from histology images, with an odds ratio of 1.710 (95% CI: 1.148-2.54). Common histologic patterns of BC were found in active or never smokers. In conclusion, deep learning reveals histopathologic features of BC that are predictive of smoke exposure and, therefore, may provide valuable information regarding smoke exposure status.
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Affiliation(s)
- Okyaz Eminaga
- AI Vobis, Palo Alto, California, United States of America
| | - Hubert Lau
- Department of Pathology and Laboratory Medicine, Veterans Affairs Palo Alto Health Care System, Palo Alto, California, United States of America
- Department of Pathology, Stanford University School of Medicine, Palo Alto, California, United States of America
| | - Eugene Shkolyar
- Department of Urology, Stanford University School of Medicine, Palo Alto, California, United States of America
| | - Eva Wardelmann
- Department of Pathology, University Hospital of Muenster, Münster, Germany
| | - Mahmoud Abbas
- Department of Pathology, University Hospital of Muenster, Münster, Germany
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9
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Cho CJ, Brown JW, Mills JC. Origins of cancer: ain't it just mature cells misbehaving? EMBO J 2024; 43:2530-2551. [PMID: 38773319 PMCID: PMC11217308 DOI: 10.1038/s44318-024-00099-0] [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: 08/26/2023] [Revised: 03/15/2024] [Accepted: 03/22/2024] [Indexed: 05/23/2024] Open
Abstract
A pervasive view is that undifferentiated stem cells are alone responsible for generating all other cells and are the origins of cancer. However, emerging evidence demonstrates fully differentiated cells are plastic, can be coaxed to proliferate, and also play essential roles in tissue maintenance, regeneration, and tumorigenesis. Here, we review the mechanisms governing how differentiated cells become cancer cells. First, we examine the unique characteristics of differentiated cell division, focusing on why differentiated cells are more susceptible than stem cells to accumulating mutations. Next, we investigate why the evolution of multicellularity in animals likely required plastic differentiated cells that maintain the capacity to return to the cell cycle and required the tumor suppressor p53. Finally, we examine an example of an evolutionarily conserved program for the plasticity of differentiated cells, paligenosis, which helps explain the origins of cancers that arise in adults. Altogether, we highlight new perspectives for understanding the development of cancer and new strategies for preventing carcinogenic cellular transformations from occurring.
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Affiliation(s)
- Charles J Cho
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Jeffrey W Brown
- Division of Gastroenterology, Department of Medicine, Washington University in St. Louis, School of Medicine, St. Louis, MO, USA
| | - Jason C Mills
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA.
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
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10
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Martínez-Pérez J, Torrado C, Domínguez-Cejudo MA, Valladares-Ayerbes M. Targeted Treatment against Cancer Stem Cells in Colorectal Cancer. Int J Mol Sci 2024; 25:6220. [PMID: 38892410 PMCID: PMC11172446 DOI: 10.3390/ijms25116220] [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: 04/27/2024] [Revised: 05/29/2024] [Accepted: 05/30/2024] [Indexed: 06/21/2024] Open
Abstract
The cancer stem cell (SC) theory proposes that a population of SCs serves as the driving force behind fundamental tumor processes, including metastasis, recurrence, and resistance to therapy. The standard of care for patients with stage III and high-risk stage II colorectal cancer (CRC) includes surgery and adjuvant chemotherapy. Fluoropyrimidines and their combination with oxaliplatin increased the cure rates, being able to eradicate the occult metastatic SC in a fraction of patients. The treatment for unresectable metastatic CRC is based on chemotherapy, antibodies to VEGF and EGFR, and tyrosine-kinase inhibitors. Immunotherapy is used in MSI-H tumors. Currently used drugs target dividing cells and, while often effective at debulking tumor mass, these agents have largely failed to cure metastatic disease. SCs are generated either due to genetic and epigenetic alterations in stem/progenitor cells or to the dedifferentiation of somatic cells where diverse signaling pathways such as Wnt/β-catenin, Hedgehog, Notch, TGF-β/SMAD, PI3K/Akt/mTOR, NF-κB, JAK/STAT, DNA damage response, and Hippo-YAP play a key role. Anti-neoplastic treatments could be improved by elimination of SCs, becoming an attractive target for the design of novel agents. Here, we present a review of clinical trials assessing the efficacy of targeted treatment focusing on these pathways in CRC.
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Affiliation(s)
- Julia Martínez-Pérez
- Medical Oncology Department, Hospital Universitario Virgen del Rocio (HUVR), Avenida de Manuel Siurot s/n, 41013 Seville, Spain;
- Institute of Biomedicine of Seville (IBiS), Hospital Universitario Virgen del Rocio (HUVR), Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Avenida de Manuel Siurot s/n, 41013 Seville, Spain;
| | - Carlos Torrado
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - María A. Domínguez-Cejudo
- Institute of Biomedicine of Seville (IBiS), Hospital Universitario Virgen del Rocio (HUVR), Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Avenida de Manuel Siurot s/n, 41013 Seville, Spain;
| | - Manuel Valladares-Ayerbes
- Medical Oncology Department, Hospital Universitario Virgen del Rocio (HUVR), Avenida de Manuel Siurot s/n, 41013 Seville, Spain;
- Institute of Biomedicine of Seville (IBiS), Hospital Universitario Virgen del Rocio (HUVR), Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Avenida de Manuel Siurot s/n, 41013 Seville, Spain;
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11
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Plante I, West DW, Weeks J, Risca VI. Simulation of Radiation-Induced DNA Damage and Protection by Histones Using the Code RITRACKS. BIOTECH 2024; 13:17. [PMID: 38921049 PMCID: PMC11201919 DOI: 10.3390/biotech13020017] [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: 03/13/2024] [Revised: 05/10/2024] [Accepted: 05/31/2024] [Indexed: 06/27/2024] Open
Abstract
(1) Background: DNA damage is of great importance in the understanding of the effects of ionizing radiation. Various types of DNA damage can result from exposure to ionizing radiation, with clustered types considered the most important for radiobiological effects. (2) Methods: The code RITRACKS (Relativistic Ion Tracks), a program that simulates stochastic radiation track structures, was used to simulate DNA damage by photons and ions spanning a broad range of linear energy transfer (LET) values. To perform these simulations, the transport code was modified to include cross sections for the interactions of ions or electrons with DNA and amino acids for ionizations, dissociative electron attachment, and elastic collisions. The radiochemistry simulations were performed using a step-by-step algorithm that follows the evolution of all particles in time, including reactions between radicals and DNA structures and amino acids. Furthermore, detailed DNA damage events, such as base pair positions, DNA fragment lengths, and fragment yields, were recorded. (3) Results: We report simulation results using photons and the ions 1H+, 4He2+, 12C6+, 16O8+, and 56Fe26+ at various energies, covering LET values from 0.3 to 164 keV/µm, and performed a comparison with other codes and experimental results. The results show evidence of DNA protection from damage at its points of contacts with histone proteins. (4) Conclusions: RITRACKS can provide a framework for studying DNA damage from a variety of ionizing radiation sources with detailed representations of DNA at the atomic scale, DNA-associated proteins, and resulting DNA damage events and statistics, enabling a broader range of future comparisons with experiments such as those based on DNA sequencing.
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Affiliation(s)
| | - Devany W. West
- Laboratory of Genome Architecture and Dynamics, The Rockefeller University, New York, NY 10065, USA; (D.W.W.); (V.I.R.)
| | - Jason Weeks
- NASA Johnson Space Center, Houston, TX 77058, USA;
| | - Viviana I. Risca
- Laboratory of Genome Architecture and Dynamics, The Rockefeller University, New York, NY 10065, USA; (D.W.W.); (V.I.R.)
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12
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Wang G, Zhang W, Ren J, Zeng Y, Dang X, Tian X, Yu W, Li Z, Ma Y, Yang P, Lu J, Zheng J, Lu B, Xu J, Liang A. The DNA damage-independent ATM signalling maintains CBP/DOT1L axis in MLL rearranged acute myeloid leukaemia. Oncogene 2024; 43:1900-1916. [PMID: 38671157 PMCID: PMC11178498 DOI: 10.1038/s41388-024-02998-2] [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: 11/21/2023] [Revised: 02/26/2024] [Accepted: 02/29/2024] [Indexed: 04/28/2024]
Abstract
The long-term maintenance of leukaemia stem cells (LSCs) is responsible for the high degree of malignancy in MLL (mixed-lineage leukaemia) rearranged acute myeloid leukaemia (AML). The DNA damage response (DDR) and DOT1L/H3K79me pathways are required to maintain LSCs in MLLr-AML, but little is known about their interplay. This study revealed that the DDR enzyme ATM regulates the maintenance of LSCs in MLLr-AML with a sequential protein-posttranslational-modification manner via CBP-DOT1L. We identified the phosphorylation of CBP by ATM, which confers the stability of CBP by preventing its proteasomal degradation, and characterised the acetylation of DOT1L by CBP, which mediates the high level of H3K79me2 for the expression of leukaemia genes in MLLr-AML. In addition, we revealed that the regulation of CBP-DOT1L axis in MLLr-AML by ATM was independent of DNA damage activation. Our findings provide insight into the signalling pathways involoved in MLLr-AML and broaden the understanding of the role of DDR enzymes beyond processing DNA damage, as well as identigying them as potent cancer targets.
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Affiliation(s)
- Guangming Wang
- Department of Hematology, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
- East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Postdoctoral Station of Clinical Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200092, China
| | - Wenjun Zhang
- Department of Hematology, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Jie Ren
- Eye & ENT Hospital, Fudan University, Shanghai, 200031, China
| | - Yu Zeng
- Department of Pathology, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Xiuyong Dang
- Department of Hematology, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Xiaoxue Tian
- Department of Hematology, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Wenlei Yu
- Department of Hematology, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Zheng Li
- Department of Hematology, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Yuting Ma
- Department of Hematology, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Pingping Yang
- Department of Hematology, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Jinyuan Lu
- Department of Hematology, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Junke Zheng
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
- Shanghai Key Laboratory of Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| | - Bing Lu
- East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
| | - Jun Xu
- East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
| | - Aibin Liang
- Department of Hematology, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China.
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13
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McConnell BB, Liang Z, Xu C, Han Y, Yun CC. LPA 5-Dependent signaling regulates regeneration of the intestinal epithelium following irradiation. Am J Physiol Gastrointest Liver Physiol 2024; 326:G631-G642. [PMID: 38593468 PMCID: PMC11376986 DOI: 10.1152/ajpgi.00269.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 03/20/2024] [Accepted: 03/30/2024] [Indexed: 04/11/2024]
Abstract
Lysophosphatidic acid (LPA) is a bioactive lipid molecule that regulates a wide array of cellular functions, including proliferation, differentiation, and survival, via activation of cognate receptors. The LPA5 receptor is highly expressed in the intestinal epithelium, but its function in restoring intestinal epithelial integrity following injury has not been examined. Here, we use a radiation-induced injury model to study the role of LPA5 in regulating intestinal epithelial regeneration. Control mice (Lpar5f/f) and mice with an inducible, epithelial cell-specific deletion of Lpar5 in the small intestine (Lpar5IECKO) were subjected to 10 Gy total body X-ray irradiation and analyzed during recovery. Repair of the intestinal mucosa was delayed in Lpar5IECKO mice with reduced epithelial proliferation and increased crypt cell apoptosis. These effects were accompanied by reduced numbers of OLFM4+ intestinal stem cells (ISCs). The effects of LPA5 on ISCs were corroborated by studies using organoids derived from Lgr5-lineage tracking reporter mice with deletion of Lpar5 in Lgr5+-stem cells (Lgr5Cont or Lgr5ΔLpar5). Irradiation of organoids resulted in fewer numbers of Lgr5ΔLpar5 organoids retaining Lgr5+-derived progenitor cells compared with Lgr5Cont organoids. Finally, we observed that impaired regeneration in Lpar5IECKO mice was associated with reduced numbers of Paneth cells and decreased expression of Yes-associated protein (YAP), a critical factor for intestinal epithelial repair. Our study highlights a novel role for LPA5 in regeneration of the intestinal epithelium following irradiation and its effect on the maintenance of Paneth cells that support the stem cell niche.NEW & NOTEWORTHY We used mice lacking expression of the lysophosphatidic acid receptor 5 (LPA5) in intestinal epithelial cells and intestinal organoids to show that the LPA5 receptor protects intestinal stem cells and progenitors from radiation-induced injury. We show that LPA5 induces YAP signaling and regulates Paneth cells.
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Affiliation(s)
- Beth B McConnell
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States
| | - Zhongxing Liang
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States
| | - Chad Xu
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States
| | - Yiran Han
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States
| | - C Chris Yun
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States
- Gastroenterology Research, Atlanta Veterans Administration Medical Center, Decatur, Georgia, United States
- Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, United States
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14
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Zhang Y, Zheng J, Chen M, Zhao S, Ma R, Chen W, Liu J. Modulating DNA damage response in uveal melanoma through embryonic stem cell microenvironment. BMC Cancer 2024; 24:519. [PMID: 38654216 DOI: 10.1186/s12885-024-12290-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: 09/04/2023] [Accepted: 04/19/2024] [Indexed: 04/25/2024] Open
Abstract
BACKGROUND Uveal melanoma (UVM) is the most common primary intraocular tumor in adults, with a median survival of 4-5 months following metastasis. DNA damage response (DDR) upregulation in UVM, which could be linked to its frequent activation of the PI3K/AKT pathway, contributes to its treatment resistance. We have reported that embryonic stem cell microenvironments (ESCMe) can revert cancer cells to less aggressive states through downregulation of the PI3K signaling, showing promise in modulating the DDR of UVM. METHODS Since nonhomologous end joining (NHEJ) is the main DNA repair mechanism in UVM, this study utilized gene expression analysis and survival prognosis analysis to investigate the role of NHEJ-related genes in UVM based on public databases. Xenograft mouse models were established to assess the therapeutic potential of ESC transplantation and exposure to ESC-conditioned medium (ESC-CM) on key DNA repair pathways in UVM. Quantitative PCR and immunohistochemistry were used to analyze NHEJ pathway-related gene expression in UVM and surrounding normal tissues. Apoptosis in UVM tissues was evaluated using the TUNEL assay. RESULTS PRKDC, KU70, XRCC5, LIG4 and PARP1 showed significant correlations with UM progression. High expression of PRKDC and XRCC5 predicted poorer overall survival, while low PARP1 and XRCC6 expression predicted better disease-free survival in UVM patients. ESCMe treatment significantly inhibited the NHEJ pathway transcriptionally and translationally and promoted apoptosis in tumor tissues in mice bearing UVM. Furthermore, ESC transplantation enhanced DDR activities in surrounding normal cells, potentially mitigating the side effects of cancer therapy. Notably, direct cell-to-cell contact with ESCs was more effective than their secreted factors in regulating the NHEJ pathway. CONCLUSIONS Our results suggest that NHEJ-related genes might serve as prognostic markers and therapeutic targets in UVM. These findings support the therapeutic potential of ESC-based therapy in enhancing UVM sensitivity to radiochemotherapy and improving treatment outcomes while minimizing damage to healthy cells.
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Affiliation(s)
- Yingxu Zhang
- Ophthalmology Department, The Tenth Affiliated Hospital, Southern Medical University (Dongguan People's Hospital), 78 Wandao Road, Dongguan, 523000, China
| | - Jinbiao Zheng
- Ophthalmology Department, The Tenth Affiliated Hospital, Southern Medical University (Dongguan People's Hospital), 78 Wandao Road, Dongguan, 523000, China
| | - Minyu Chen
- Ophthalmology Department, The Tenth Affiliated Hospital, Southern Medical University (Dongguan People's Hospital), 78 Wandao Road, Dongguan, 523000, China
| | - Shulun Zhao
- Ophthalmology Department, The Tenth Affiliated Hospital, Southern Medical University (Dongguan People's Hospital), 78 Wandao Road, Dongguan, 523000, China
| | - Ruiqian Ma
- Ophthalmology Department, The Tenth Affiliated Hospital, Southern Medical University (Dongguan People's Hospital), 78 Wandao Road, Dongguan, 523000, China
| | - Wenwei Chen
- Ophthalmology Department, The Tenth Affiliated Hospital, Southern Medical University (Dongguan People's Hospital), 78 Wandao Road, Dongguan, 523000, China
| | - Jiahui Liu
- Ophthalmology Department, The Tenth Affiliated Hospital, Southern Medical University (Dongguan People's Hospital), 78 Wandao Road, Dongguan, 523000, China.
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15
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Liu L, Zhang M, Cui N, Liu W, Di G, Wang Y, Xi X, Li H, Shen Z, Gu M, Wang Z, Jiang S, Liu B. Integration of single-cell RNA-seq and bulk RNA-seq to construct liver hepatocellular carcinoma stem cell signatures to explore their impact on patient prognosis and treatment. PLoS One 2024; 19:e0298004. [PMID: 38635528 PMCID: PMC11025768 DOI: 10.1371/journal.pone.0298004] [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: 11/13/2023] [Accepted: 01/11/2024] [Indexed: 04/20/2024] Open
Abstract
BACKGROUND Liver hepatocellular carcinoma (LIHC) is a prevalent form of primary liver cancer. Research has demonstrated the contribution of tumor stem cells in facilitating tumor recurrence, metastasis, and treatment resistance. Despite this, there remains a lack of established cancer stem cells (CSCs)-associated genes signatures for effectively predicting the prognosis and guiding the treatment strategies for patients diagnosed with LIHC. METHODS The single-cell RNA sequencing (scRNA-seq) and bulk RNA transcriptome data were obtained based on public datasets and computerized firstly using CytoTRACE package and One Class Linear Regression (OCLR) algorithm to evaluate stemness level, respectively. Then, we explored the association of stemness indicators (CytoTRACE score and stemness index, mRNAsi) with survival outcomes and clinical characteristics by combining clinical information and survival analyses. Subsequently, weighted co-expression network analysis (WGCNA) and Cox were applied to assess mRNAsi-related genes in bulk LIHC data and construct a prognostic model for LIHC patients. Single-sample gene-set enrichment analysis (ssGSEA), Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) and Tumor Immune Estimation Resource (TIMER) analysis were employed for immune infiltration assessment. Finally, the potential immunotherapeutic response was predicted by the Tumor Immune Dysfunction and Exclusion (TIDE), and the tumor mutation burden (TMB). Additionally, pRRophetic package was applied to evaluate the sensitivity of high and low-risk groups to common chemotherapeutic drugs. RESULTS A total of four genes (including STIP1, H2AFZ, BRIX1, and TUBB) associated with stemness score (CytoTRACE score and mRNAsi) were identified and constructed a risk model that could predict prognosis in LIHC patients. It was observed that high stemness cells occurred predominantly in the late stages of LIHC and that poor overall survival in LIHC patients was also associated with high mRNAsi scores. In addition, pathway analysis confirmed the biological uniqueness of the two risk groups. Personalized treatment predictions suggest that patients with a low risk benefited more from immunotherapy, while those with a high risk group may be conducive to chemotherapeutic drugs. CONCLUSION The current study developed a novel prognostic risk signature with genes related to CSCs, which provides novel ideas for the diagnosis, prognosis and treatment of LIHC.
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Affiliation(s)
- Lixia Liu
- Department of Ultrasound and Hebei Key Laboratory of Precise Imaging of Inflammation Related Tumors, Affiliated Hospital of Hebei University, Baoding, 071052, China
| | - Meng Zhang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Hebei University, Baoding, 071052, China
| | - Naipeng Cui
- Department of Breast Surgery, Affiliated Hospital of Hebei University, Baoding, 071052, China
| | - Wenwen Liu
- Department of Breast Surgery, Affiliated Hospital of Hebei University, Baoding, 071052, China
| | - Guixin Di
- Department of Ultrasound, Affiliated Hospital of Hebei University, Baoding, 071052, China
| | - Yanan Wang
- Department of Pathology, Affiliated Hospital of Hebei University, Baoding, 071052, China
| | - Xin Xi
- Central Laboratory, Hebei Key Laboratory of Cancer Radiotherapy and Chemotherapy, Affiliated Hospital of Hebei University, Baoding, 071052, China
| | - Hao Li
- Central Laboratory, Hebei Key Laboratory of Cancer Radiotherapy and Chemotherapy, Affiliated Hospital of Hebei University, Baoding, 071052, China
| | - Zhou Shen
- Central Laboratory, Hebei Key Laboratory of Cancer Radiotherapy and Chemotherapy, Affiliated Hospital of Hebei University, Baoding, 071052, China
| | - Miaomiao Gu
- Department of Ultrasound, Affiliated Hospital of Hebei University, Baoding, 071052, China
| | - Zichao Wang
- Department of Ultrasound, Affiliated Hospital of Hebei University, Baoding, 071052, China
| | - Shan Jiang
- Central Laboratory, Hebei Key Laboratory of Cancer Radiotherapy and Chemotherapy, Affiliated Hospital of Hebei University, Baoding, 071052, China
| | - Bin Liu
- Central Laboratory, Hebei Key Laboratory of Cancer Radiotherapy and Chemotherapy, Affiliated Hospital of Hebei University, Baoding, 071052, China
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Cao X, Yan Z, Chen Z, Ge Y, Hu X, Peng F, Huang W, Zhang P, Sun R, Chen J, Ding M, Zong D, He X. The Emerging Role of Deubiquitinases in Radiosensitivity. Int J Radiat Oncol Biol Phys 2024; 118:1347-1370. [PMID: 38092257 DOI: 10.1016/j.ijrobp.2023.12.003] [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: 08/11/2023] [Revised: 11/03/2023] [Accepted: 12/03/2023] [Indexed: 02/05/2024]
Abstract
Radiation therapy is a primary treatment for cancer, but radioresistance remains a significant challenge in improving efficacy and reducing toxicity. Accumulating evidence suggests that deubiquitinases (DUBs) play a crucial role in regulating cell sensitivity to ionizing radiation. Traditional small-molecule DUB inhibitors have demonstrated radiosensitization effects, and novel deubiquitinase-targeting chimeras (DUBTACs) provide a promising strategy for radiosensitizer development by harnessing the ubiquitin-proteasome system. This review highlights the mechanisms by which DUBs regulate radiosensitivity, including DNA damage repair, the cell cycle, cell death, and hypoxia. Progress on DUB inhibitors and DUBTACs is summarized, and their potential radiosensitization effects are discussed. Developing drugs targeting DUBs appears to be a promising alternative approach to overcoming radioresistance, warranting further research into their mechanisms.
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Affiliation(s)
- Xiang Cao
- Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, and Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, China
| | - Zhenyu Yan
- Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, and Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, China
| | - Zihan Chen
- Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Yizhi Ge
- Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, and Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, China
| | - Xinyu Hu
- Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, and Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, China
| | - Fanyu Peng
- Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, and Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, China
| | - Wenxuan Huang
- Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, and Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, China
| | - Pingchuan Zhang
- Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, and Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, China
| | - Ruozhou Sun
- Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, and Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, China
| | - Jiazhen Chen
- Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, and Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, China
| | - Mingjun Ding
- Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, and Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, China
| | - Dan Zong
- Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, and Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, China.
| | - Xia He
- Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, and Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, China; Xuzhou Medical University, Xuzhou, Jiangsu, China; Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.
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17
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Liang X, Zhou J, Li C, Wang H, Wan Y, Ling C, Pu L, Zhang W, Fan M, Hong J, Zhai Z. The roles and mechanisms of TGFB1 in acute myeloid leukemia chemoresistance. Cell Signal 2024; 116:111027. [PMID: 38171389 DOI: 10.1016/j.cellsig.2023.111027] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 12/06/2023] [Accepted: 12/27/2023] [Indexed: 01/05/2024]
Abstract
Relapsed or Refractory (R/R) Acute Myeloid Leukemia (AML) patients usually have very poor prognoses, and drug-resistance is one of the major limiting factors. In this study, we aimed to explore the functions of Transforming Growth Factor-β1 (TGFB1) in AML drug-resistance. First, TGFB1 levels in serum and bone marrow are higher in R/R patients compared with newly diagnosed patients, this phenomenon could be due to different sources of secreted TGFB1 according to immunohistochemistry of marrow biopsies. Similarly, TGFB1 expression in AML drug-resistant cell lines is higher than that in their parental cell lines, and blocking the TGFB signaling pathway by specific inhibitors decreased resistance to chemotherapeutic agents. On the other hand, exogenous TGFB1 can also promote AML parental cells senescence and chemotherapy resistance. Next, we found SOX4 level is upregulated in drug-resistant cells, and parental cells treated with exogenous TGFB1 induced upregulation of SOX4 levels. Interference of SOX4 expression by siRNA diminished the TGFB1-induced sensitivity to chemotherapeutic agents. Finally, we conduct metabolomic analysis and find Alanine, aspartate and glutamate metabolism pathway, and Glycerophospholipid metabolism pathway are decreased after inhibiting TGFB signaling pathway or interfering SOX4 expression. This study concludes that TGFB1 level in R/R AML patients and drug-resistant strains is significantly increased. Blocking the TGFB signaling pathway can enhance the chemosensitivity of drug-resistant cells by suppressing SOX4 expression and metabolic reprogramming.
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Affiliation(s)
- Xue Liang
- Hematologic Department/Hematologic Disease Research Center, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Ji Zhou
- Department of Epidemiology and Health Statistics, Anhui Medical University, School of Public Health, Hefei, Anhui, China; School of Nursing, Anhui Medical University, Hefei, Anhui, China
| | - Cong Li
- Hematologic Department/Hematologic Disease Research Center, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Huiping Wang
- Hematologic Department/Hematologic Disease Research Center, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Yang Wan
- Hematologic Department/Hematologic Disease Research Center, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Chun Ling
- Hematologic Department/Hematologic Disease Research Center, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Lianfang Pu
- Hematologic Department/Hematologic Disease Research Center, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Wanqiu Zhang
- Hematologic Department/Hematologic Disease Research Center, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Mengmeng Fan
- Hematologic Department/Hematologic Disease Research Center, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Jingfang Hong
- Department of Epidemiology and Health Statistics, Anhui Medical University, School of Public Health, Hefei, Anhui, China; School of Nursing, Anhui Medical University, Hefei, Anhui, China
| | - Zhimin Zhai
- Hematologic Department/Hematologic Disease Research Center, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
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18
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Swann JW, Olson OC, Passegué E. Made to order: emergency myelopoiesis and demand-adapted innate immune cell production. Nat Rev Immunol 2024:10.1038/s41577-024-00998-7. [PMID: 38467802 DOI: 10.1038/s41577-024-00998-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/18/2024] [Indexed: 03/13/2024]
Abstract
Definitive haematopoiesis is the process by which haematopoietic stem cells, located in the bone marrow, generate all haematopoietic cell lineages in healthy adults. Although highly regulated to maintain a stable output of blood cells in health, the haematopoietic system is capable of extensive remodelling in response to external challenges, prioritizing the production of certain cell types at the expense of others. In this Review, we consider how acute insults, such as infections and cytotoxic drug-induced myeloablation, cause molecular, cellular and metabolic changes in haematopoietic stem and progenitor cells at multiple levels of the haematopoietic hierarchy to drive accelerated production of the mature myeloid cells needed to resolve the initiating insult. Moreover, we discuss how dysregulation or subversion of these emergency myelopoiesis mechanisms contributes to the progression of chronic inflammatory diseases and cancer.
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Affiliation(s)
- James W Swann
- Columbia Stem Cell Initiative, Department of Genetics and Development, Columbia University, New York, NY, USA
| | - Oakley C Olson
- Columbia Stem Cell Initiative, Department of Genetics and Development, Columbia University, New York, NY, USA
| | - Emmanuelle Passegué
- Columbia Stem Cell Initiative, Department of Genetics and Development, Columbia University, New York, NY, USA.
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19
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Caipa Garcia AL, Kucab JE, Al-Serori H, Beck RSS, Bellamri M, Turesky RJ, Groopman JD, Francies HE, Garnett MJ, Huch M, Drost J, Zilbauer M, Arlt VM, Phillips DH. Tissue Organoid Cultures Metabolize Dietary Carcinogens Proficiently and Are Effective Models for DNA Adduct Formation. Chem Res Toxicol 2024; 37:234-247. [PMID: 38232180 PMCID: PMC10880098 DOI: 10.1021/acs.chemrestox.3c00255] [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: 08/23/2023] [Revised: 12/21/2023] [Accepted: 01/04/2024] [Indexed: 01/19/2024]
Abstract
Human tissue three-dimensional (3D) organoid cultures have the potential to reproduce in vitro the physiological properties and cellular architecture of the organs from which they are derived. The ability of organoid cultures derived from human stomach, liver, kidney, and colon to metabolically activate three dietary carcinogens, aflatoxin B1 (AFB1), aristolochic acid I (AAI), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), was investigated. In each case, the response of a target tissue (liver for AFB1; kidney for AAI; colon for PhIP) was compared with that of a nontarget tissue (gastric). After treatment cell viabilities were measured, DNA damage response (DDR) was determined by Western blotting for p-p53, p21, p-CHK2, and γ-H2AX, and DNA adduct formation was quantified by mass spectrometry. Induction of the key xenobiotic-metabolizing enzymes (XMEs) CYP1A1, CYP1A2, CYP3A4, and NQO1 was assessed by qRT-PCR. We found that organoids from different tissues can activate AAI, AFB1, and PhIP. In some cases, this metabolic potential varied between tissues and between different cultures of the same tissue. Similarly, variations in the levels of expression of XMEs were observed. At comparable levels of cytotoxicity, organoids derived from tissues that are considered targets for these carcinogens had higher levels of adduct formation than a nontarget tissue.
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Affiliation(s)
- Angela L. Caipa Garcia
- Department
of Analytical, Environmental and Forensic Sciences, School of Cancer
& Pharmaceutical Sciences, King’s
College London, London SE1 9NH, U.K.
| | - Jill E. Kucab
- Department
of Analytical, Environmental and Forensic Sciences, School of Cancer
& Pharmaceutical Sciences, King’s
College London, London SE1 9NH, U.K.
| | - Halh Al-Serori
- Department
of Analytical, Environmental and Forensic Sciences, School of Cancer
& Pharmaceutical Sciences, King’s
College London, London SE1 9NH, U.K.
| | - Rebekah S. S. Beck
- Department
of Analytical, Environmental and Forensic Sciences, School of Cancer
& Pharmaceutical Sciences, King’s
College London, London SE1 9NH, U.K.
| | - Madjda Bellamri
- Department
of Medicinal Chemistry, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, United States
| | - Robert J. Turesky
- Department
of Medicinal Chemistry, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, United States
| | - John D. Groopman
- Department
of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, United States
| | | | | | - Meritxell Huch
- Max
Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany
| | - Jarno Drost
- Princess
Máxima Center for Pediatric Oncology, Oncode Institute, 3584
CS Utrecht, The Netherlands
| | - Matthias Zilbauer
- Department
of Paediatrics, University of Cambridge, Cambridge CB2 0QQ, U.K.
| | - Volker M. Arlt
- Department
of Analytical, Environmental and Forensic Sciences, School of Cancer
& Pharmaceutical Sciences, King’s
College London, London SE1 9NH, U.K.
| | - David H. Phillips
- Department
of Analytical, Environmental and Forensic Sciences, School of Cancer
& Pharmaceutical Sciences, King’s
College London, London SE1 9NH, U.K.
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20
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Ma JY, Xia TJ, Li S, Yin S, Luo SM, Li G. Germline cell de novo mutations and potential effects of inflammation on germline cell genome stability. Semin Cell Dev Biol 2024; 154:316-327. [PMID: 36376195 DOI: 10.1016/j.semcdb.2022.11.003] [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: 07/14/2022] [Revised: 11/05/2022] [Accepted: 11/06/2022] [Indexed: 11/13/2022]
Abstract
Uncontrolled pathogenic genome mutations in germline cells might impair adult fertility, lead to birth defects or even affect the adaptability of a species. Understanding the sources of DNA damage, as well as the features of damage response in germline cells are the overarching tasks to reduce the mutations in germline cells. With the accumulation of human genome data and genetic reports, genome variants formed in germline cells are being extensively explored. However, the sources of DNA damage, the damage repair mechanisms, and the effects of DNA damage or mutations on the development of germline cells are still unclear. Besides exogenous triggers of DNA damage such as irradiation and genotoxic chemicals, endogenous exposure to inflammation may also contribute to the genome instability of germline cells. In this review, we summarized the features of de novo mutations and the specific DNA damage responses in germline cells and explored the possible roles of inflammation on the genome stability of germline cells.
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Affiliation(s)
- Jun-Yu Ma
- Fertility Preservation Lab, Guangdong-Hong Kong Metabolism & Reproduction Joint Laboratory, Reproductive Medicine Center, Guangdong Second Provincial General Hospital, Guangzhou, China.
| | - Tian-Jin Xia
- Fertility Preservation Lab, Guangdong-Hong Kong Metabolism & Reproduction Joint Laboratory, Reproductive Medicine Center, Guangdong Second Provincial General Hospital, Guangzhou, China; College of Life Sciences, Qingdao Agricultural University, Qingdao, China
| | - Shuai Li
- Center for Clinical Epidemiology and Methodology, Guangdong Second Provincial General Hospital, Guangzhou, China
| | - Shen Yin
- College of Life Sciences, Qingdao Agricultural University, Qingdao, China.
| | - Shi-Ming Luo
- Fertility Preservation Lab, Guangdong-Hong Kong Metabolism & Reproduction Joint Laboratory, Reproductive Medicine Center, Guangdong Second Provincial General Hospital, Guangzhou, China.
| | - Guowei Li
- Center for Clinical Epidemiology and Methodology, Guangdong Second Provincial General Hospital, Guangzhou, China.
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21
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Mills M, Emori C, Kumar P, Boucher Z, George J, Bolcun-Filas E. Single-cell and bulk transcriptional profiling of mouse ovaries reveals novel genes and pathways associated with DNA damage response in oocytes. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.02.02.578648. [PMID: 38352597 PMCID: PMC10862846 DOI: 10.1101/2024.02.02.578648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/23/2024]
Abstract
Immature oocytes enclosed in primordial follicles stored in female ovaries are under constant threat of DNA damage induced by endogenous and exogenous factors. Checkpoint kinase 2 (CHEK2) is a key mediator of the DNA damage response in all cells. Genetic studies have shown that CHEK2 and its downstream targets, p53 and TAp63, regulate primordial follicle elimination in response to DNA damage, however the mechanism leading to their demise is still poorly characterized. Single-cell and bulk RNA sequencing were used to determine the DNA damage response in wildtype and Chek2-deficient ovaries. A low but oocyte-lethal dose of ionizing radiation induces a DNA damage response in ovarian cells that is solely dependent on CHEK2. DNA damage activates multiple ovarian response pathways related to apoptosis, p53, interferon signaling, inflammation, cell adhesion, and intercellular communication. These pathways are differentially employed by different ovarian cell types, with oocytes disproportionately affected by radiation. Novel genes and pathways are induced by radiation specifically in oocytes, shedding light on their sensitivity to DNA damage, and implicating a coordinated response between oocytes and pre-granulosa cells within the follicle. These findings provide a foundation for future studies on the specific mechanisms regulating oocyte survival in the context of aging, as well as therapeutic and environmental genotoxic exposures.
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Affiliation(s)
- Monique Mills
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
- The Graduate School of Biomedical Science and Engineering, University of Maine, Orono, ME 04469, USA
| | - Chihiro Emori
- Department of Experimental Genome Research, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 5650871, Japan
| | - Parveen Kumar
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
| | - Zachary Boucher
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
| | - Joshy George
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
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22
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Kim M, Jang HJ, Baek SY, Choi KJ, Han DH, Sung JS. Regulation of base excision repair during adipogenesis and osteogenesis of bone marrow-derived mesenchymal stem cells. Sci Rep 2023; 13:16384. [PMID: 37773206 PMCID: PMC10542337 DOI: 10.1038/s41598-023-43737-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 09/27/2023] [Indexed: 10/01/2023] Open
Abstract
Bone marrow-derived human mesenchymal stem cells (hMSCs) can differentiate into various lineages, such as chondrocytes, adipocytes, osteoblasts, and neuronal lineages. It has been shown that the high-efficiency DNA-repair capacity of hMSCs is decreased during their differentiation. However, the underlying its mechanism during adipogenesis and osteogenesis is unknown. Herein, we investigated how alkyl-damage repair is modulated during adipogenic and osteogenic differentiation, especially focusing on the base excision repair (BER) pathway. Response to an alkylation agent was assessed via quantification of the double-strand break (DSB) foci and activities of BER-related enzymes during differentiation in hMSCs. Adipocytes showed high resistance against methyl methanesulfonate (MMS)-induced alkyl damage, whereas osteoblasts were more sensitive than hMSCs. During the differentiation, activities, and protein levels of uracil-DNA glycosylase were found to be regulated. In addition, ligation-related proteins, such as X-ray repair cross-complementing protein 1 (XRCC1) and DNA polymerase β, were upregulated in adipocytes, whereas their levels and recruitment declined during osteogenesis. These modulations of BER enzyme activity during differentiation influenced DNA repair efficiency and the accumulation of DSBs as repair intermediates in the nucleus. Taken together, we suggest that BER enzymatic activity is regulated in adipogenic and osteogenic differentiation and these alterations in the BER pathway led to different responses to alkyl damage from those in hMSCs.
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Affiliation(s)
- Min Kim
- Department of Life Science, Dongguk University-Seoul, Biomedi Campus, 32 Dongguk-ro, Ilsandong-gu, Goyang, Gyeonggi-do, 10326, Republic of Korea
| | - Hyun-Jin Jang
- Department of Life Science, Dongguk University-Seoul, Biomedi Campus, 32 Dongguk-ro, Ilsandong-gu, Goyang, Gyeonggi-do, 10326, Republic of Korea
| | - Song-Yi Baek
- Department of Life Science, Dongguk University-Seoul, Biomedi Campus, 32 Dongguk-ro, Ilsandong-gu, Goyang, Gyeonggi-do, 10326, Republic of Korea
| | - Kyung-Jin Choi
- Department of Life Science, Dongguk University-Seoul, Biomedi Campus, 32 Dongguk-ro, Ilsandong-gu, Goyang, Gyeonggi-do, 10326, Republic of Korea
| | - Dong-Hee Han
- Department of Life Science, Dongguk University-Seoul, Biomedi Campus, 32 Dongguk-ro, Ilsandong-gu, Goyang, Gyeonggi-do, 10326, Republic of Korea
| | - Jung-Suk Sung
- Department of Life Science, Dongguk University-Seoul, Biomedi Campus, 32 Dongguk-ro, Ilsandong-gu, Goyang, Gyeonggi-do, 10326, Republic of Korea.
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23
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Wang P, Kljavin N, Nguyen TTT, Storm EE, Marsh B, Jiang J, Lin W, Menon H, Piskol R, de Sauvage FJ. Adrenergic nerves regulate intestinal regeneration through IL-22 signaling from type 3 innate lymphoid cells. Cell Stem Cell 2023; 30:1166-1178.e8. [PMID: 37597516 DOI: 10.1016/j.stem.2023.07.013] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 06/23/2023] [Accepted: 07/25/2023] [Indexed: 08/21/2023]
Abstract
The intestinal epithelium has high intrinsic turnover rate, and the precise renewal of the epithelium is dependent on the microenvironment. The intestine is innervated by a dense network of peripheral nerves that controls various aspects of intestinal physiology. However, the role of neurons in regulating epithelial cell regeneration remains largely unknown. Here, we investigated the effects of gut-innervating adrenergic nerves on epithelial cell repair following irradiation (IR)-induced injury. We observed that adrenergic nerve density in the small intestine increased post IR, while chemical adrenergic denervation impaired epithelial regeneration. Single-cell RNA sequencing experiments revealed a decrease in IL-22 signaling post IR in denervated animals. Combining pharmacologic and genetic tools, we demonstrate that β-adrenergic receptor signaling drives IL-22 production from type 3 innate lymphoid cells (ILC3s) post IR, which in turn promotes epithelial regeneration. These results define an adrenergic-ILC3 axis important for intestinal regeneration.
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Affiliation(s)
- Putianqi Wang
- Molecular Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
| | - Noelyn Kljavin
- Molecular Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
| | - Thi Thu Thao Nguyen
- Oncology Bioinformatics, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
| | - Elaine E Storm
- Molecular Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
| | - Bryan Marsh
- Molecular Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
| | - Jian Jiang
- Research Pathology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
| | - William Lin
- Research Pathology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
| | - Hari Menon
- Microchemistry, Proteomics, Lipidomics and Next Generation Sequencing, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
| | - Robert Piskol
- Oncology Bioinformatics, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
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24
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Garimella SV, Gampa SC, Chaturvedi P. Mitochondria in Cancer Stem Cells: From an Innocent Bystander to a Central Player in Therapy Resistance. Stem Cells Cloning 2023; 16:19-41. [PMID: 37641714 PMCID: PMC10460581 DOI: 10.2147/sccaa.s417842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Accepted: 08/15/2023] [Indexed: 08/31/2023] Open
Abstract
Cancer continues to rank among the world's leading causes of mortality despite advancements in treatment. Cancer stem cells, which can self-renew, are present in low abundance and contribute significantly to tumor recurrence, tumorigenicity, and drug resistance to various therapies. The drug resistance observed in cancer stem cells is attributed to several factors, such as cellular quiescence, dormancy, elevated aldehyde dehydrogenase activity, apoptosis evasion mechanisms, high expression of drug efflux pumps, protective vascular niche, enhanced DNA damage response, scavenging of reactive oxygen species, hypoxic stability, and stemness-related signaling pathways. Multiple studies have shown that mitochondria play a pivotal role in conferring drug resistance to cancer stem cells, through mitochondrial biogenesis, metabolism, and dynamics. A better understanding of how mitochondria contribute to tumorigenesis, heterogeneity, and drug resistance could lead to the development of innovative cancer treatments.
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Affiliation(s)
- Sireesha V Garimella
- Department of Biotechnology, School of Science, GITAM (Deemed to be University), Visakhapatnam, Andhra Pradesh, 530045, India
| | - Siri Chandana Gampa
- Department of Biotechnology, School of Science, GITAM (Deemed to be University), Visakhapatnam, Andhra Pradesh, 530045, India
| | - Pankaj Chaturvedi
- Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
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25
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Perillo M, Punzo A, Caliceti C, Sell C, Lorenzini A. The spontaneous immortalization probability of mammalian cell culture strains, as their proliferative capacity, correlates with species body mass, not longevity. Biomed J 2023; 46:100596. [PMID: 37149260 PMCID: PMC10277518 DOI: 10.1016/j.bj.2023.100596] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 04/21/2023] [Accepted: 04/29/2023] [Indexed: 05/08/2023] Open
Abstract
BACKGROUND The Peto's paradox consists in the observation that individuals from long-lived and large animal species do not experience a higher cancer incidence, despite being exposed for longer time to the possibility of accumulating mutations and having more target cells exposed to the phenomenon. The existence of this paradox has been recently confirmed (Vincze et al., 2022). Concurrently, robust evidence has been published that longevity involves a convergent evolution of cellular mechanisms that prevent the accumulation of mutations (Cagan et al., 2022). It remains unclear which cellular mechanisms are critical to allow the evolution of a large body mass while keeping cancer at bay. METHODS Adding to existing data linking cellular replicative potential and species body mass (Lorenzini et al., 2005), we have grown a total of 84 skin fibroblast cell strains from 40 donors of 17 mammalian species and analyzed their Hayflick's limit, i.e., their senescent plateau, and eventual spontaneous immortalization escape. The correlation of immortalization and replicative capacity of the species with their longevity, body mass and metabolism has been assessed through phylogenetic multiple linear regression (MLR). RESULTS The immortalization probability is negatively related to species body mass. The new evaluation and additional data about replicative potential strengthen our previous observation, confirming that stable and extended proliferation is strongly correlated with the evolution of a large body mass rather than lifespan. CONCLUSION The relation between immortalization and body mass suggests a need to evolve stringent mechanisms that control genetic stability during the evolution of a large body mass.
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Affiliation(s)
- Matteo Perillo
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy.
| | - Angela Punzo
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy
| | - Cristiana Caliceti
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy
| | - Christian Sell
- Department of Biochemistry & Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Antonello Lorenzini
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy
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26
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Atmakuru PS, Dhawan J. The cilium-centrosome axis in coupling cell cycle exit and cell fate. J Cell Sci 2023; 136:308872. [PMID: 37144419 DOI: 10.1242/jcs.260454] [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] [Indexed: 05/06/2023] Open
Abstract
The centrosome is an evolutionarily conserved, ancient organelle whose role in cell division was first described over a century ago. The structure and function of the centrosome as a microtubule-organizing center, and of its extracellular extension - the primary cilium - as a sensory antenna, have since been extensively studied, but the role of the cilium-centrosome axis in cell fate is still emerging. In this Opinion piece, we view cellular quiescence and tissue homeostasis from the vantage point of the cilium-centrosome axis. We focus on a less explored role in the choice between distinct forms of mitotic arrest - reversible quiescence and terminal differentiation, which play distinct roles in tissue homeostasis. We outline evidence implicating the centrosome-basal body switch in stem cell function, including how the cilium-centrosome complex regulates reversible versus irreversible arrest in adult skeletal muscle progenitors. We then highlight exciting new findings in other quiescent cell types that suggest signal-dependent coupling of nuclear and cytoplasmic events to the centrosome-basal body switch. Finally, we propose a framework for involvement of this axis in mitotically inactive cells and identify future avenues for understanding how the cilium-centrosome axis impacts central decisions in tissue homeostasis.
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Affiliation(s)
- Priti S Atmakuru
- CSIR Centre for Cellular and Molecular Biology, Hyderabad 500 007, India
| | - Jyotsna Dhawan
- CSIR Centre for Cellular and Molecular Biology, Hyderabad 500 007, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
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27
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Weeden CE, Hill W, Lim EL, Grönroos E, Swanton C. Impact of risk factors on early cancer evolution. Cell 2023; 186:1541-1563. [PMID: 37059064 DOI: 10.1016/j.cell.2023.03.013] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 01/31/2023] [Accepted: 03/14/2023] [Indexed: 04/16/2023]
Abstract
Recent identification of oncogenic cells within healthy tissues and the prevalence of indolent cancers found incidentally at autopsies reveal a greater complexity in tumor initiation than previously appreciated. The human body contains roughly 40 trillion cells of 200 different types that are organized within a complex three-dimensional matrix, necessitating exquisite mechanisms to restrain aberrant outgrowth of malignant cells that have the capacity to kill the host. Understanding how this defense is overcome to trigger tumorigenesis and why cancer is so extraordinarily rare at the cellular level is vital to future prevention therapies. In this review, we discuss how early initiated cells are protected from further tumorigenesis and the non-mutagenic pathways by which cancer risk factors promote tumor growth. By nature, the absence of permanent genomic alterations potentially renders these tumor-promoting mechanisms clinically targetable. Finally, we consider existing strategies for early cancer interception with perspectives on the next steps for molecular cancer prevention.
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Affiliation(s)
- Clare E Weeden
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK
| | - William Hill
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK
| | - Emilia L Lim
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Cancer Research UK Lung Cancer Center of Excellence, University College London Cancer Institute, London, UK
| | - Eva Grönroos
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK
| | - Charles Swanton
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Cancer Research UK Lung Cancer Center of Excellence, University College London Cancer Institute, London, UK; Department of Oncology, University College London Hospitals, London, UK.
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28
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Shiroor DA, Wang KT, Sanketi BD, Tapper JK, Adler CE. Inhibition of ATM kinase rescues planarian regeneration after lethal radiation. EMBO Rep 2023; 24:e56112. [PMID: 36943023 PMCID: PMC10157310 DOI: 10.15252/embr.202256112] [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: 09/11/2022] [Revised: 02/20/2023] [Accepted: 02/27/2023] [Indexed: 03/23/2023] Open
Abstract
As stem cells divide, they acquire mutations that can be passed on to daughter cells. To mitigate potentially deleterious outcomes, cells activate the DNA damage response (DDR) network, which governs several cellular outcomes following DNA damage, including repairing DNA or undergoing apoptosis. At the helm of the DDR are three PI3-like kinases including Ataxia-Telangiectasia Mutated (ATM). We report here that knockdown of ATM in planarian flatworms enables stem cells to withstand lethal doses of radiation which would otherwise induce cell death. In this context, stem cells circumvent apoptosis, replicate their DNA, and recover function using homologous recombination-mediated DNA repair. Despite radiation exposure, atm knockdown animals survive long-term and regenerate new tissues. These effects occur independently of ATM's canonical downstream effector p53. Together, our results demonstrate that in planarians, ATM promotes radiation-induced apoptosis. This acute, ATM-dependent apoptosis is a key determinant of long-term animal survival. Our results suggest that inhibition of ATM in these organisms could, therefore, potentially favor cell survival after radiation without obvious effects on stem cell behavior.
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Affiliation(s)
- Divya A Shiroor
- Department of Molecular Medicine, Cornell University College of Veterinary Medicine, Ithaca, NY, USA
| | - Kuang-Tse Wang
- Department of Molecular Medicine, Cornell University College of Veterinary Medicine, Ithaca, NY, USA
| | - Bhargav D Sanketi
- Department of Molecular Medicine, Cornell University College of Veterinary Medicine, Ithaca, NY, USA
| | - Justin K Tapper
- Department of Molecular Medicine, Cornell University College of Veterinary Medicine, Ithaca, NY, USA
| | - Carolyn E Adler
- Department of Molecular Medicine, Cornell University College of Veterinary Medicine, Ithaca, NY, USA
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29
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Sipos F, Műzes G. Cancer Stem Cell Relationship with Pro-Tumoral Inflammatory Microenvironment. Biomedicines 2023; 11:189. [PMID: 36672697 PMCID: PMC9855358 DOI: 10.3390/biomedicines11010189] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 01/05/2023] [Accepted: 01/10/2023] [Indexed: 01/15/2023] Open
Abstract
Inflammatory processes and cancer stem cells (CSCs) are increasingly recognized as factors in the development of tumors. Emerging evidence indicates that CSCs are associated with cancer properties such as metastasis, treatment resistance, and disease recurrence. However, the precise interaction between CSCs and the immune microenvironment remains unexplored. Although evasion of the immune system by CSCs has been extensively studied, new research demonstrates that CSCs can also control and even profit from the immune response. This review provides an overview of the reciprocal interplay between CSCs and tumor-infiltrating immune cells, collecting pertinent data about how CSCs stimulate leukocyte reprogramming, resulting in pro-tumor immune cells that promote metastasis, chemoresistance, tumorigenicity, and even a rise in the number of CSCs. Tumor-associated macrophages, neutrophils, Th17 and regulatory T cells, mesenchymal stem cells, and cancer-associated fibroblasts, as well as the signaling pathways involved in these pro-tumor activities, are among the immune cells studied. Although cytotoxic leukocytes have the potential to eliminate CSCs, immune evasion mechanisms in CSCs and their clinical implications are also known. We intended to compile experimental findings that provide direct evidence of interactions between CSCs and the immune system and CSCs and the inflammatory milieu. In addition, we aimed to summarize key concepts in order to comprehend the cross-talk between CSCs and the tumor microenvironment as a crucial process for the effective design of anti-CSC therapies.
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Affiliation(s)
| | - Györgyi Műzes
- Immunology Division, Department of Internal Medicine and Hematology, Semmelweis University, 1085 Budapest, Hungary
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30
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Wu J, Feng J, Zhang Q, He Y, Xu C, Wang C, Li W. Epigenetic regulation of stem cells in lung cancer oncogenesis and therapy resistance. Front Genet 2023; 14:1120815. [PMID: 37144123 PMCID: PMC10151750 DOI: 10.3389/fgene.2023.1120815] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Accepted: 02/22/2023] [Indexed: 05/06/2023] Open
Abstract
Epigenetics plays an important role in regulating stem cell signaling, as well as in the oncogenesis of lung cancer and therapeutic resistance. Determining how to employ these regulatory mechanisms to treat cancer is an intriguing medical challenge. Lung cancer is caused by signals that cause aberrant differentiation of stem cells or progenitor cells. The different pathological subtypes of lung cancer are determined by the cells of origin. Additionally, emerging studies have demonstrated that the occurrence of cancer treatment resistance is connected to the hijacking of normal stem cell capability by lung cancer stem cells, especially in the processes of drug transport, DNA damage repair, and niche protection. In this review, we summarize the principles of the epigenetic regulation of stem cell signaling in relation to the emergence of lung cancer and resistance to therapy. Furthermore, several investigations have shown that the tumor immune microenvironment in lung cancer affects these regulatory pathways. And ongoing experiments on epigenetics-related therapeutic strategies provide new insight for the treatment of lung cancer in the future.
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Affiliation(s)
- Jiayang Wu
- Department of Pulmonary and Critical Care Medicine, Med-X Center for Manufacturing, Center of Precision Medicine, Precision Medicine Key Laboratory of Sichuan Province, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China
| | - Jiaming Feng
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Qiran Zhang
- Department of Pulmonary and Critical Care Medicine, Med-X Center for Manufacturing, Center of Precision Medicine, Precision Medicine Key Laboratory of Sichuan Province, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China
| | - Yazhou He
- Department of oncology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
- Department of Oncology, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Chuan Xu
- Department of Oncology, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Chengdi Wang
- Department of Pulmonary and Critical Care Medicine, Med-X Center for Manufacturing, Center of Precision Medicine, Precision Medicine Key Laboratory of Sichuan Province, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China
- *Correspondence: Weimin Li, ; Chengdi Wang,
| | - Weimin Li
- Department of Pulmonary and Critical Care Medicine, Med-X Center for Manufacturing, Center of Precision Medicine, Precision Medicine Key Laboratory of Sichuan Province, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China
- *Correspondence: Weimin Li, ; Chengdi Wang,
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31
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Le W, Zhou F, Xiang J, Weng Y, Wu D, Xu J, Zhang J. Preliminary Study on 53BP1-Mediated DNA Double-Strand Break Response in Spermatogonial Stem Cells. Reprod Sci 2022; 30:1572-1584. [PMID: 36446980 DOI: 10.1007/s43032-022-01122-7] [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: 08/13/2022] [Accepted: 10/30/2022] [Indexed: 11/30/2022]
Abstract
53BP1 mediates DNA repair process in somatic cells; however, the function of 53BP1 in germline stem cells still remains unclear. In the present study, animals and cells DNA damage repair (DDR) model was established by irradiation and HU treatment; immunofluorescence staining and laser confocal microscopy were used to detect the expression of 53BP1, p-CHK2, and p-P53 in the DDR process of mSSCs. 53BP1 knockdown expression mSSCs cell line conducted by Trp53bp1-shRNA was established and EdU staining was adopted to analyze cell cycle and cell proliferation. Moreover, NHEJ reporter vector was applied to detect the repair efficacy after Trp53bp1 knocked-down (KD) expression. Results showed that 53BP1 could form foci signals in mSSCs during DDR process both in vivo and in vitro, which was independent of γH2AX. 53BP1 downstream protein, p-P53, and p-CHK2 were involved and dynamically expressed in DDR response. Knocking down of Trp53bp1 expression in mSSCs could not dramatically inhibit cell proliferation, but may increase cell sensitivity to HU. The NHEJ repair efficacy was sharply decreased in Trp53bp-KD SSCs via flow cytometry analysis. We revealed the specific mechanism of 53BP1 in SSCs DDR process, which is expected to provide a new theoretical basis and insights for the diagnosis and treatment of male infertility.
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Affiliation(s)
- Wei Le
- Department of Urology, Tongji Hospital, Tongji University School of Medicine, 389 Xincun Road, Shanghai, 200065, China
| | - Fang Zhou
- Department of Surgery, Tongren Hospital, Shanghai Jiaotong University School of Medicine, 1111 Xianxia Road, Shanghai, 200050, China
| | - Jun Xiang
- Department of Urology, Tongji Hospital, Tongji University School of Medicine, 389 Xincun Road, Shanghai, 200065, China
| | - Yiming Weng
- Department of Reproductive Medicine, Tongji Hospital, Tongji University School of Medicine, 389 Xincun Road, Shanghai, 200065, China
| | - Denglong Wu
- Department of Urology, Tongji Hospital, Tongji University School of Medicine, 389 Xincun Road, Shanghai, 200065, China
| | - Jun Xu
- Department of Regenerative Medicine, East Hospital, Tongji University School of Medicine, 1239 Siping Road, Shanghai, 200120, China
| | - Jinfu Zhang
- Department of Reproductive Medicine, Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 540 Xinhua Road, Shanghai, 200052, China.
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32
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Lu Y, Zhang X. Radiochemotherapy-induced DNA repair promotes the biogenesis of gastric cancer stem cells. Stem Cell Res Ther 2022; 13:481. [PMID: 36153608 PMCID: PMC9509583 DOI: 10.1186/s13287-022-03165-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 08/28/2022] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Clinically, metastasis and recurrence occurred after routine radiochemotherapy in dozens of cases of gastric cancer, mainly attributed to the role of cancer stem cells (CSCs). Actually, radiochemotherapy could induce DNA damages, leading to activation of DNA repair which might be associated with acquisition of stem cell phenotype. Hitherto, the contribution made by active DNA repair to stemness induction has not been extensively explored. METHODS Cisplatin/doxorubicin treatment and X-ray exposure were conducted in gastric cancer cell lines and gastric cancer cells derived from solid tumors to model clinical therapy. Quantitative real-time PCR, Western blot, and tumorsphere/tumor formation assay were further used to characterize CSCs and assess activation of DNA repair. RNA-seq was performed to identify which DNA repair genes were crucial for CSC traits induction, followed by the investigation of underlying mechanism and functional significance via in vitro and in vivo experiments. RESULTS Here, we report a mechanism through which gastric cancer cells in response to radiochemotherapy were reprogrammed into gastric cancer stem cell-like cells. In this mechanism, radiochemotherapy triggers DNA damage response accompanied by elevated levels of EID3, a typical DNA repair gene, which interacts with NAMPT to promote stemness via upregulating Wnt signaling pathway, manifested by enhanced tumorsphere/tumor formation in gastric cancer. In addition to involvement of EID3 in stemness acquisition, it also shows impacts on proliferation, cell cycle, apoptosis and therapy resistance to maintain the characteristics of CSC populations. CONCLUSION Our study indicates that gastric cancer cells can be endowed with stemness traits via EID3-NAMPT-Wnt/β-catenin axis in response to radiochemotherapy. Blocking this axis (i.e., targeting EID3) along with radiochemotherapy might represent a potential strategy to sensitize CSCs to radiochemotherapy and further reinforce the anti-tumor effects of conventional treatments.
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Affiliation(s)
- Yu Lu
- College of Life Sciences, Laboratory for Marine Biology and Biotechnology of Pilot National Laboratory for Marine Science and Technology (Qingdao) and Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhejiang University, Hangzhou, 310058, People's Republic of China
| | - Xiaobo Zhang
- College of Life Sciences, Laboratory for Marine Biology and Biotechnology of Pilot National Laboratory for Marine Science and Technology (Qingdao) and Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhejiang University, Hangzhou, 310058, People's Republic of China.
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33
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Liu D, Dong S, Liu C, Du J, Wang S, Yu H, Li W, Chen Z, Peng R, Jiang Q, Zou M, Li F, Zhang R. CRX-527 induced differentiation of HSCs protecting the intestinal epithelium from radiation damage. Front Immunol 2022; 13:927213. [PMID: 36110845 PMCID: PMC9468934 DOI: 10.3389/fimmu.2022.927213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Accepted: 07/26/2022] [Indexed: 11/13/2022] Open
Abstract
Recently, Toll-like receptors (TLRs) have been extensively studied in radiation damage, but the inherent defects of high toxicity and low efficacy of most TLR ligands limit their further clinical transformation. CRX-527, as a TLR4 ligand, has rarely been reported to protect against radiation. We demonstrated that CRX-527 was safer than LPS at the same dose in vivo and had almost no toxic effect in vitro. Administration of CRX-527 improved the survival rate of total body irradiation (TBI) to 100% in wild-type mice but not in TLR4-/- mice. After TBI, hematopoietic system damage was significantly alleviated, and the recovery period was accelerated in CRX-527-treated mice. Moreover, CRX-527 induced differentiation of HSCs and the stimulation of CRX-527 significantly increased the proportion and number of LSK cells and promoted their differentiation into macrophages, activating immune defense. Furthermore, we proposed an immune defense role for hematopoietic differentiation in the protection against intestinal radiation damage, and confirmed that macrophages invaded the intestines through peripheral blood to protect them from radiation damage. Meanwhile, CRX-527 maintained intestinal function and homeostasis, promoted the regeneration of intestinal stem cells, and protected intestinal injury from lethal dose irradiation. Furthermore, After the use of mice, we found that CRX-527 had no significant protective effect on the hematopoietic and intestinal systems of irradiated TLR4-/- mice. in conclusion, CRX-527 induced differentiation of HSCs protecting the intestinal epithelium from radiation damage.
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Affiliation(s)
- Dongshu Liu
- Postgraduate Training Base of the People's Liberation Army (PLA) of China Rocket Force Characteristic Medical Center, Jinzhou Medical University, Beijing, China
| | - Suhe Dong
- People's Liberation Army (PLA) of China Rocket Force Characteristic Medical Center, Beijing, China
| | - Cong Liu
- Naval Medical University, Shanghai, China
| | - Jicong Du
- Naval Medical University, Shanghai, China
| | - Sinian Wang
- People's Liberation Army (PLA) of China Rocket Force Characteristic Medical Center, Beijing, China
| | - Huijie Yu
- People's Liberation Army (PLA) of China Rocket Force Characteristic Medical Center, Beijing, China
| | - Wei Li
- People's Liberation Army (PLA) of China Rocket Force Characteristic Medical Center, Beijing, China
| | - Zhongmin Chen
- People's Liberation Army (PLA) of China Rocket Force Characteristic Medical Center, Beijing, China
| | - Renjun Peng
- People's Liberation Army (PLA) of China Rocket Force Characteristic Medical Center, Beijing, China
| | - Qisheng Jiang
- People's Liberation Army (PLA) of China Rocket Force Characteristic Medical Center, Beijing, China
| | - Mengying Zou
- People's Liberation Army (PLA) of China Rocket Force Characteristic Medical Center, Beijing, China
| | - Fengsheng Li
- People's Liberation Army (PLA) of China Rocket Force Characteristic Medical Center, Beijing, China
| | - Rong Zhang
- Postgraduate Training Base of the People's Liberation Army (PLA) of China Rocket Force Characteristic Medical Center, Jinzhou Medical University, Beijing, China
- People's Liberation Army (PLA) of China Rocket Force Characteristic Medical Center, Beijing, China
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34
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Marongiu F, DeGregori J. The sculpting of somatic mutational landscapes by evolutionary forces and their impacts on aging-related disease. Mol Oncol 2022; 16:3238-3258. [PMID: 35726685 PMCID: PMC9490148 DOI: 10.1002/1878-0261.13275] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/29/2022] [Accepted: 05/19/2022] [Indexed: 12/19/2022] Open
Abstract
Aging represents the major risk factor for the development of cancer and many other diseases. Recent findings show that normal tissues become riddled with expanded clones that are frequently driven by cancer‐associated mutations in an aging‐dependent fashion. Additional studies show how aged tissue microenvironments promote the initiation and progression of malignancies, while young healthy tissues actively suppress the outgrowth of malignant clones. Here, we discuss conserved mechanisms that eliminate poorly functioning or potentially malignant cells from our tissues to maintain organismal health and fitness. Natural selection acts to preserve tissue function and prevent disease to maximize reproductive success but these mechanisms wane as reproduction becomes less likely. The ensuing age‐dependent tissue decline can impact the shape and direction of clonal somatic evolution, with lifestyle and exposures influencing its pace and intensity. We also consider how aging‐ and exposure‐dependent clonal expansions of “oncogenic” mutations might both increase cancer risk late in life and contribute to tissue decline and non‐malignant disease. Still, we can marvel at the ability of our bodies to avoid cancers and other diseases despite the accumulation of billions of cells with cancer‐associated mutations.
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Affiliation(s)
- Fabio Marongiu
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.,Department of Biomedical Sciences, Section of Pathology, University of Cagliari, Italy
| | - James DeGregori
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.,University of Colorado Comprehensive Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
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35
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Liu FR, Jiang MJ, Mei Z, Lin CJ, Tian L. cGAS-STING signalings potentiate tumor progression via sustaining cancer stemness. Transl Oncol 2022; 20:101404. [PMID: 35364558 PMCID: PMC8968062 DOI: 10.1016/j.tranon.2022.101404] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 03/07/2022] [Accepted: 03/20/2022] [Indexed: 12/19/2022] Open
Abstract
Intrinsic activation of cGAS-STING signalings potentiate tumorigenesis. cGAS-STING signalings promote tumor progression by sustaining cancer stemness. STAT3 may act as a downstream effector of cGAS-STING signalings to stimulate cancer stemness. The cytosolic DNA-sensing cGAS-STING pathway has been proved to be involved in tumor progression and influence the effect of cancer immunotherapy. However, little attentions have been paid to the role of cGAS-STING pathway on cancer stemness. Herein, we found that the cGAS-STING pathway was activated in different tumor cells. cGAS- or STING-knockout impaired the capability of tumor formation in vivo and tumorsphere formation in vitro. In addition, loss of cGAS-STING cascade promoted tumor apoptosis, but inhibited tumor growth and metastasis. We further demonstrated that cGAS-STING pathway potentiated tumor formation by sustaining cancer stemness. Moreover, analysis of RNA-seq showed that cGAS-STING pathway maintained cancer stemness probably by activating STAT3. Our findings highlight the role of intrinsic activation of cGAS-STING pathway in tumorigenesis, and reveal a new mechanism of its regulation of tumor progression via sustaining cancer stemness through STAT3 activation.
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36
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Flynn MJ, Ledermann JA. Ovarian cancer recurrence: is the definition of platinum resistance modified by PARPi and other intervening treatments? The evolving landscape in the management of platinum-resistant ovarian cancer. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2022; 5:424-435. [PMID: 35800366 PMCID: PMC9255242 DOI: 10.20517/cdr.2022.13] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 03/30/2022] [Accepted: 04/11/2022] [Indexed: 11/13/2022]
Abstract
Definitions of platinum resistance have been questioned and changed over the last five years, even though no predictive biomarker of resistance exists. These have sculpted how we approach platinum retreatment and, consequently, how we devise new treatment strategies for those patients with tumour progression on platinum therapy. Platinum-non-eligible ovarian cancer is treated with single-agent non-platinum drugs. When bevacizumab can be added to chemotherapy, progression-free survival improves significantly. For patients with a BRCA mutation, PARP inhibitor monotherapy is an option compared to chemotherapy. There is currently no clearly identified role for immune-checkpoint inhibition in this patient population. This review describes some of the challenges in treating patients with platinum resistance and suggests refinements in the selection of patients most likely to benefit from targeting a DNA damage response, angiogenesis or immune modulation. It also describes novel agents of interest and possible mechanisms of the synergy of therapeutic combinations.
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Affiliation(s)
- Michael J. Flynn
- Department of Oncology, University College London Hospital, London NW1 2PG, United Kingdom
| | - Jonathan A. Ledermann
- Department of Oncology, University College London Hospital, London NW1 2PG, United Kingdom
- UCL Cancer Institute, University College London, London WC1E 6DD, United Kingdom
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37
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Haldavnekar R, Ganesh S, Venkatakrishnan K, Tan B. Cancer Stem Cell DNA Enabled Real-Time Genotyping with Self-Functionalized Quantum Superstructures-Overcoming the Barriers of Noninvasive cfDNA Cancer Diagnostics. SMALL METHODS 2022; 6:e2101467. [PMID: 35247038 DOI: 10.1002/smtd.202101467] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 02/11/2022] [Indexed: 06/14/2023]
Abstract
Cancer diagnosis and determining its tissue of origin are crucial for clinical implementation of personalized medicine. Conventional diagnostic techniques such as imaging and tissue biopsy are unable to capture the dynamic tumor landscape. Although circulating tumor DNA (ctDNA) shows promise for diagnosis, the clinical relevance of ctDNA remains largely undetermined due to several biological and technical complexities. Here, cancer stem cell-ctDNA is used to overcome the biological complexities like the inability for molecular analysis of ctDNA and dependence on ctDNA concentration rather than the molecular profile. Ultrasensitive quantum superstructures overcome the technical complexities of trace-level detection and rapid diagnosis to detect ctDNA within its short half-life. Activation of multiple surface enhanced Raman scattering mechanisms of the quantum superstructures achieved a very high enhancement factor (1.35 × 1011 ) and detection at ultralow concentration (10-15 M) with very high reliability (RSD: 3-12%). Pilot validation with clinical plasma samples from an independent validation cohort achieved a diagnosis sensitivity of ≈95% and specificity of 83%. Quantum superstructures identified the tissue of origin with ≈75-86% sensitivity and ≈92-96% specificity. With large scale clinical validation, the technology can develop into a clinically useful liquid biopsy tool improving cancer diagnostics.
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Affiliation(s)
- Rupa Haldavnekar
- Institute for Biomedical Engineering, Science and Technology (I BEST), Partnership between Ryerson University and St. Michael's Hospital, Toronto, ON, M5B 1W8, Canada
- Ultrashort Laser Nanomanufacturing Research Facility, Faculty of Engineering and Architectural Sciences, Ryerson University, Toronto, ON, M5B 2K3, Canada
- Nanocharacterization Laboratory, Faculty of Engineering and Architectural Sciences, Ryerson University, Toronto, ON, M5B 2K3, Canada
- Nano-Bio Interface facility, Faculty of Engineering and Architectural Sciences, Ryerson University, Toronto, ON, M5B 2K3, Canada
| | - Swarna Ganesh
- Institute for Biomedical Engineering, Science and Technology (I BEST), Partnership between Ryerson University and St. Michael's Hospital, Toronto, ON, M5B 1W8, Canada
- Ultrashort Laser Nanomanufacturing Research Facility, Faculty of Engineering and Architectural Sciences, Ryerson University, Toronto, ON, M5B 2K3, Canada
- Nanocharacterization Laboratory, Faculty of Engineering and Architectural Sciences, Ryerson University, Toronto, ON, M5B 2K3, Canada
- Nano-Bio Interface facility, Faculty of Engineering and Architectural Sciences, Ryerson University, Toronto, ON, M5B 2K3, Canada
| | - Krishnan Venkatakrishnan
- Institute for Biomedical Engineering, Science and Technology (I BEST), Partnership between Ryerson University and St. Michael's Hospital, Toronto, ON, M5B 1W8, Canada
- Ultrashort Laser Nanomanufacturing Research Facility, Faculty of Engineering and Architectural Sciences, Ryerson University, Toronto, ON, M5B 2K3, Canada
- Nanocharacterization Laboratory, Faculty of Engineering and Architectural Sciences, Ryerson University, Toronto, ON, M5B 2K3, Canada
- Nano-Bio Interface facility, Faculty of Engineering and Architectural Sciences, Ryerson University, Toronto, ON, M5B 2K3, Canada
- Keenan Research Center for Biomedical Science, Unity Health Toronto, Toronto, ON, M5B 1W8, Canada
| | - Bo Tan
- Institute for Biomedical Engineering, Science and Technology (I BEST), Partnership between Ryerson University and St. Michael's Hospital, Toronto, ON, M5B 1W8, Canada
- Nanocharacterization Laboratory, Faculty of Engineering and Architectural Sciences, Ryerson University, Toronto, ON, M5B 2K3, Canada
- Keenan Research Center for Biomedical Science, Unity Health Toronto, Toronto, ON, M5B 1W8, Canada
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Ren J, Wang X, Dong C, Wang G, Zhang W, Cai C, Qian M, Yang D, Ling B, Ning K, Mao Z, Liu B, Wang T, Xiong L, Wang W, Liang A, Gao Z, Xu J. Sirt1 protects subventricular zone derived neural stem cells from DNA double strand breaks and contributes to olfactory function maintenance in aging mice. Stem Cells 2022; 40:493-507. [PMID: 35349711 DOI: 10.1093/stmcls/sxac008] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 12/09/2021] [Indexed: 11/12/2022]
Abstract
Abstract
DNA damage is assumed to accumulate in stem cells over time and their ability to withstand this damage and maintain tissue homeostasis is a key determinant of aging. Nonetheless, relatively few studies have investigated whether DNA damage does indeed accumulate in stem cells and whether this contributes to stem cell aging and functional decline. Here, we found that, compared with young mice, DNA double strand breaks (DSBs) are reduced in subventricular zone (SVZ)-derived neural stem cells (NSCs) of aged mice, which was achieved partly through the adaptive upregulation of Sirt1 expression and non-homologous end joining (NHEJ)-mediated DNA repair. Sirt1 deficiency abolished this effect, leading to stem cell exhaustion, olfactory memory decline, and accelerated aging. The reduced DSBs and the upregulation of Sirt1 expression in SVZ-derived NSCs with age may represent a compensatory mechanism that evolved to protect stem cells from excessive DNA damage, as well as mitigate memory loss and other stresses during aging.
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Affiliation(s)
- Jie Ren
- East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
- Department of Neuroscience, Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK
| | - Xianli Wang
- State Key Laboratory of Oncogenes and Related Genes, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Chuanming Dong
- Department of Anatomy, Nantong University, Nantong, People's Republic of China
| | - Guangming Wang
- Department of Hematology, Tongji Hospital of Tongji University School of Medicine, Shanghai, People's Republic of China
- Postdoctoral Station of Clinical Medicine, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Wenjun Zhang
- Department of Hematology, Tongji Hospital of Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Chunhui Cai
- Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Minxian Qian
- Medical Research Center, Department of Biochemistry and Molecular Biology, Shenzhen University Health Science Center, Shenzhen, People's Republic of China
| | - Danjing Yang
- East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Bin Ling
- Department of Intensive Care Unit, Affiliated Hospital of Yunnan University (The Second People's Hospital of Yunnan Province), Kunming, People's Republic of China
| | - Ke Ning
- Department of Neuroscience, Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK
| | - Zhiyong Mao
- School of Life Science and Technology, Tongji University, Shanghai, People's Republic of China
| | - Baohua Liu
- Medical Research Center, Department of Biochemistry and Molecular Biology, Shenzhen University Health Science Center, Shenzhen, People's Republic of China
| | - Tinghua Wang
- Animal Center of Zoology, Institute of Neuroscience, Kunming Medical University, Kunming, People's Republic of China
| | - Liuliu Xiong
- Animal Center of Zoology, Institute of Neuroscience, Kunming Medical University, Kunming, People's Republic of China
| | - Wenyuan Wang
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, Shanghai, People's Republic of China
- Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Aibin Liang
- Department of Hematology, Tongji Hospital of Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Zhengliang Gao
- Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), Tongji University School of Medicine, Shanghai, People's Republic of China
- Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong, People's Republic of China
| | - Jun Xu
- East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
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Rocheteau P, Warot G, Chapellier M, Zampaolo M, Chretien F, Piquemal F. Cryopreserved Stem Cells Incur Damages Due To Terrestrial Cosmic Rays Impairing Their Integrity Upon Long-Term Storage. Cell Transplant 2022; 31:9636897211070239. [PMID: 35170351 PMCID: PMC8855380 DOI: 10.1177/09636897211070239] [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] [Indexed: 12/05/2022] Open
Abstract
Stem cells have the capacity to ensure the renewal of tissues and organs. They
could be used in the future for a wide range of therapeutic purposes and are
preserved at liquid nitrogen temperature to prevent any chemical or biological
activity up to several decades before their use. We show that the cryogenized
cells accumulate damages coming from natural radiations, potentially inducing
DNA double-strand breaks (DSBs). Such DNA damage in stem cells could lead to
either mortality of the cells upon thawing or a mutation diminishing the
therapeutic potential of the treatment. Many studies show how stem cells react
to different levels of radiation; the effect of terrestrial cosmic rays being
key, it is thus also important to investigate the effect of the natural
radiation on the cryopreserved stem cell behavior over time. Our study showed
that the cryostored stem cells totally shielded from cosmic rays had less DSBs
upon long-term storage. This could have important implications on the long-term
cryostorage strategy and quality control of different cell banks.
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Affiliation(s)
- P Rocheteau
- Human Histopathology and Animal Models, Department of Infection & Epidemiology, Institut Pasteur, Paris, France
| | - G Warot
- Laboratoire de Physique Subatomique et Corpusculaire, UMR 5821, Université Grenoble Alpes, Centre National de la Recherche Scientifique, Grenoble Institute of Technology (Institute of Engineering University Grenoble Alpes), LPSC-IN2P3, Grenoble, France
| | - M Chapellier
- Laboratoire de Physique Subatomique et Corpusculaire, UMR 5821, Université Grenoble Alpes, Centre National de la Recherche Scientifique, Grenoble Institute of Technology (Institute of Engineering University Grenoble Alpes), LPSC-IN2P3, Grenoble, France
| | - M Zampaolo
- Laboratoire de Physique Subatomique et Corpusculaire, UMR 5821, Université Grenoble Alpes, Centre National de la Recherche Scientifique, Grenoble Institute of Technology (Institute of Engineering University Grenoble Alpes), LPSC-IN2P3, Grenoble, France
| | - F Chretien
- Human Histopathology and Animal Models, Department of Infection & Epidemiology, Institut Pasteur, Paris, France
| | - F Piquemal
- Centre d'Etudes Nucléaires de Bordeaux Gradignan, UMR 5797, Centre National de la Recherche Scientifique and Université de Bordeaux, Gradignan, France
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40
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Azzoni V, Wicinski J, Macario M, Castagné M, Finetti P, Ambrosova K, Rouault CD, Sergé A, Farina A, Agavnian E, Coslet S, Josselin E, Guille A, Adelaide J, Zacharioudakis E, Castellano R, Bertucci F, Birnbaum D, Rodriguez R, Charafe-Jauffret E, Ginestier C. BMI1 nuclear location is critical for RAD51-dependent response to replication stress and drives chemoresistance in breast cancer stem cells. Cell Death Dis 2022; 13:96. [PMID: 35110528 PMCID: PMC8811067 DOI: 10.1038/s41419-022-04538-w] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 12/21/2021] [Accepted: 01/17/2022] [Indexed: 12/22/2022]
Abstract
Replication stress (RS) has a pivotal role in tumor initiation, progression, or therapeutic resistance. In this study, we depicted the mechanism of breast cancer stem cells’ (bCSCs) response to RS and its clinical implication. We demonstrated that bCSCs present a limited level of RS compared with non-bCSCs in patient samples. We described for the first time that the spatial nuclear location of BMI1 protein triggers RS response in breast cancers. Hence, in bCSCs, BMI1 is rapidly located to stalled replication forks to recruit RAD51 and activate homologous-recombination machinery, whereas in non-bCSCs BMI1 is trapped on demethylated 1q12 megasatellites precluding effective RS response. We further demonstrated that BMI1/RAD51 axis activation is necessary to prevent cisplatin-induced DNA damage and that treatment of patient-derived xenografts with a RAD51 inhibitor sensitizes tumor-initiating cells to cisplatin. The comprehensive view of replicative-stress response in bCSC has profound implications for understanding and improving therapeutic resistance.
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Affiliation(s)
- Violette Azzoni
- Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Epithelial Stem Cells and Cancer Lab, "Equipe labellisée Ligue Contre le Cancer", Marseille, France
| | - Julien Wicinski
- Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Epithelial Stem Cells and Cancer Lab, "Equipe labellisée Ligue Contre le Cancer", Marseille, France
| | - Manon Macario
- Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Epithelial Stem Cells and Cancer Lab, "Equipe labellisée Ligue Contre le Cancer", Marseille, France
| | - Martin Castagné
- Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Epithelial Stem Cells and Cancer Lab, "Equipe labellisée Ligue Contre le Cancer", Marseille, France
| | - Pascal Finetti
- Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Predictive Oncology, "Equipe labellisée Ligue Contre le Cancer", Marseille, France
| | - Katerina Ambrosova
- Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Epithelial Stem Cells and Cancer Lab, "Equipe labellisée Ligue Contre le Cancer", Marseille, France
| | - Célia D Rouault
- Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Epithelial Stem Cells and Cancer Lab, "Equipe labellisée Ligue Contre le Cancer", Marseille, France
| | - Arnaud Sergé
- Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, leuko/stromal interactions in normal and pathological hematopoiesis Lab, Marseille, France
| | - Anne Farina
- Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Experimental Pathology Platform, Marseille, France
| | - Emilie Agavnian
- Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Experimental Pathology Platform, Marseille, France
| | - Sergiu Coslet
- Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Experimental Pathology Platform, Marseille, France
| | - Emmanuelle Josselin
- Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, TrGET Plateform, Marseille, France
| | - Arnaud Guille
- Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Predictive Oncology, "Equipe labellisée Ligue Contre le Cancer", Marseille, France
| | - José Adelaide
- Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Predictive Oncology, "Equipe labellisée Ligue Contre le Cancer", Marseille, France
| | - Emmanouil Zacharioudakis
- Institut Curie, CNRS, INSERM, PSL Research University, Chemical Cell Biology Group, Paris, France
| | - Rémy Castellano
- Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, TrGET Plateform, Marseille, France
| | - Francois Bertucci
- Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Predictive Oncology, "Equipe labellisée Ligue Contre le Cancer", Marseille, France
| | - Daniel Birnbaum
- Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Predictive Oncology, "Equipe labellisée Ligue Contre le Cancer", Marseille, France
| | - Raphael Rodriguez
- Institut Curie, CNRS, INSERM, PSL Research University, Chemical Cell Biology Group, Paris, France
| | - Emmanuelle Charafe-Jauffret
- Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Epithelial Stem Cells and Cancer Lab, "Equipe labellisée Ligue Contre le Cancer", Marseille, France.
| | - Christophe Ginestier
- Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Epithelial Stem Cells and Cancer Lab, "Equipe labellisée Ligue Contre le Cancer", Marseille, France.
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Mianné J, Nasri A, Van CN, Bourguignon C, Fieldès M, Ahmed E, Duthoit C, Martin N, Parrinello H, Louis A, Iché A, Gayon R, Samain F, Lamouroux L, Bouillé P, Bourdin A, Assou S, De Vos J. CRISPR/Cas9-mediated gene knockout and interallelic gene conversion in human induced pluripotent stem cells using non-integrative bacteriophage-chimeric retrovirus-like particles. BMC Biol 2022; 20:8. [PMID: 34996449 PMCID: PMC8742436 DOI: 10.1186/s12915-021-01214-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 12/02/2021] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND The application of CRISPR/Cas9 technology in human induced pluripotent stem cells (hiPSC) holds tremendous potential for basic research and cell-based gene therapy. However, the fulfillment of these promises relies on the capacity to efficiently deliver exogenous nucleic acids and harness the repair mechanisms induced by the nuclease activity in order to knock-out or repair targeted genes. Moreover, transient delivery should be preferred to avoid persistent nuclease activity and to decrease the risk of off-target events. We recently developed bacteriophage-chimeric retrovirus-like particles that exploit the properties of bacteriophage coat proteins to package exogenous RNA, and the benefits of lentiviral transduction to achieve highly efficient, non-integrative RNA delivery in human cells. Here, we investigated the potential of bacteriophage-chimeric retrovirus-like particles for the non-integrative delivery of RNA molecules in hiPSC for CRISPR/Cas9 applications. RESULTS We found that these particles efficiently convey RNA molecules for transient expression in hiPSC, with minimal toxicity and without affecting the cell pluripotency and subsequent differentiation. We then used this system to transiently deliver in a single step the CRISPR-Cas9 components (Cas9 mRNA and sgRNA) to generate gene knockout with high indel rate (up to 85%) at multiple loci. Strikingly, when using an allele-specific sgRNA at a locus harboring compound heterozygous mutations, the targeted allele was not altered by NHEJ/MMEJ, but was repaired at high frequency using the homologous wild type allele, i.e., by interallelic gene conversion. CONCLUSIONS Our results highlight the potential of bacteriophage-chimeric retrovirus-like particles to efficiently and safely deliver RNA molecules in hiPSC, and describe for the first time genome engineering by gene conversion in hiPSC. Harnessing this DNA repair mechanism could facilitate the therapeutic correction of human genetic disorders in hiPSC.
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Affiliation(s)
- Joffrey Mianné
- IRMB, Univ Montpellier, INSERM, CHU Montpellier, Hôpital St Eloi, 80 avenue Augustin Fliche, 34295, Montpellier, France
| | - Amel Nasri
- IRMB, Univ Montpellier, INSERM, CHU Montpellier, Hôpital St Eloi, 80 avenue Augustin Fliche, 34295, Montpellier, France
| | - Chloé Nguyen Van
- IRMB, Univ Montpellier, INSERM, CHU Montpellier, Hôpital St Eloi, 80 avenue Augustin Fliche, 34295, Montpellier, France
| | - Chloé Bourguignon
- IRMB, Univ Montpellier, INSERM, CHU Montpellier, Hôpital St Eloi, 80 avenue Augustin Fliche, 34295, Montpellier, France
| | - Mathieu Fieldès
- IRMB, Univ Montpellier, INSERM, CHU Montpellier, Hôpital St Eloi, 80 avenue Augustin Fliche, 34295, Montpellier, France
| | - Engi Ahmed
- IRMB, Univ Montpellier, INSERM, CHU Montpellier, Hôpital St Eloi, 80 avenue Augustin Fliche, 34295, Montpellier, France
| | | | | | - Hugues Parrinello
- Univ. Montpellier, CNRS, INSERM, Montpellier, France
- MGX-Montpellier GenomiX, Univ. Montpellier, CNRS, INSERM, Montpellier, France
| | - Anaïs Louis
- Univ. Montpellier, CNRS, INSERM, Montpellier, France
- MGX-Montpellier GenomiX, Univ. Montpellier, CNRS, INSERM, Montpellier, France
| | | | | | | | | | | | - Arnaud Bourdin
- PhyMedExp, Univ Montpellier, INSERM, CHU Montpellier, Montpellier, France
| | - Said Assou
- IRMB, Univ Montpellier, INSERM, CHU Montpellier, Hôpital St Eloi, 80 avenue Augustin Fliche, 34295, Montpellier, France
| | - John De Vos
- IRMB, Univ Montpellier, INSERM, CHU Montpellier, Hôpital St Eloi, 80 avenue Augustin Fliche, 34295, Montpellier, France.
- Department of Cell and Tissue Engineering, Univ Montpellier, CHU Montpellier, Montpellier, France.
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42
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Kato T, Liu N, Morinaga H, Asakawa K, Muraguchi T, Muroyama Y, Shimokawa M, Matsumura H, Nishimori Y, Tan LJ, Hayano M, Sinclair DA, Mohri Y, Nishimura EK. Dynamic stem cell selection safeguards the genomic integrity of the epidermis. Dev Cell 2021; 56:3309-3320.e5. [PMID: 34932948 DOI: 10.1016/j.devcel.2021.11.018] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 09/14/2021] [Accepted: 11/16/2021] [Indexed: 12/31/2022]
Abstract
Maintaining genomic integrity and stability is crucial for life; yet, no tissue-driven mechanism that robustly safeguards the epithelial genome has been discovered. Epidermal stem cells (EpiSCs) continuously replenish the stratified layers of keratinocytes that protect organisms against various environmental stresses. To study the dynamics of DNA-damaged cells in tissues, we devised an in vivo fate tracing system for EpiSCs with DNA double-strand breaks (DSBs) and demonstrated that those cells exit from their niches. The clearance of EpiSCs with DSBs is caused by selective differentiation and delamination through the DNA damage response (DDR)-p53-Notch/p21 axis, with the downregulation of ITGB1. Moreover, concomitant enhancement of symmetric cell divisions of surrounding stem cells indicates that the selective elimination of cells with DSBs is coupled with the augmented clonal expansion of intact stem cells. These data collectively demonstrate that tissue autonomy through the dynamic coupling of cell-autonomous and non-cell-autonomous mechanisms coordinately maintains the genomic quality of the epidermis.
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Affiliation(s)
- Tomoki Kato
- Department of Stem Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Nan Liu
- Department of Stem Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Hironobu Morinaga
- Department of Stem Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Kyosuke Asakawa
- Department of Stem Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan; Division of Aging and Regeneration, Institute of Medical Science, the University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
| | - Taichi Muraguchi
- Department of Stem Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Yuko Muroyama
- Department of Stem Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Mariko Shimokawa
- Department of Stem Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Hiroyuki Matsumura
- Department of Stem Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Yuriko Nishimori
- Department of Stem Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Li Jing Tan
- Department of Stem Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Motoshi Hayano
- Department of Genetics, Blavatnik Institute, Paul F. Glenn Center for Biology of Aging Research, Harvard Medical School, Boston, MA, USA; Department of Neuropsychiatry, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan; Faculty of Science and Technology, Keio University, Yokohama, Japan
| | - David A Sinclair
- Department of Genetics, Blavatnik Institute, Paul F. Glenn Center for Biology of Aging Research, Harvard Medical School, Boston, MA, USA; Laboratory for Ageing Research, Department of Pharmacology, School of Medical Sciences, The University of New South Wales, Sydney, New South Wales, Australia
| | - Yasuaki Mohri
- Department of Stem Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan; Division of Aging and Regeneration, Institute of Medical Science, the University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
| | - Emi K Nishimura
- Department of Stem Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan; Division of Aging and Regeneration, Institute of Medical Science, the University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
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43
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Dong C, Wang X, Sun L, Zhu L, Yang D, Gao S, Zhang W, Ling B, Liang A, Gao Z, Xu J. ATM modulates subventricular zone neural stem cell maintenance and senescence through Notch signaling pathway. Stem Cell Res 2021; 58:102618. [PMID: 34915311 DOI: 10.1016/j.scr.2021.102618] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Revised: 09/22/2021] [Accepted: 12/06/2021] [Indexed: 12/20/2022] Open
Abstract
Ataxia telangiectasia mutated (ATM) plays an essential role in DNA damage response and the maintenance of genomic stability. However, the role of ATM in regulating the function of adult neural stem cells (NSCs) remains unclear. Here we report that ATM deficiency led to accumulated DNA damage and decreased DNA damage repair capacity in neural progenitor cells. Moreover, we observed ATM ablation lead to the short-term increase of proliferation of neural progenitor cells, resulting in the depletion of the NSC pool over time, and this loss of NSC quiescence resulted in accelerated cell senescence. We further apply RNA sequencing to unravel that ATM knockout significantly affected Notch signaling pathway, furthermore, notch activation inhibit the abnormal increased proliferation of ATM-/- NSCs. Taken together, these findings indicate that ATM can serve as a key regulator for the normal function of adult NSCs by maintaining their stemness and preventing cellular senescence primarily through Notch signaling pathway.
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Affiliation(s)
- Chuanming Dong
- Department of Anatomy, Nantong University, Nantong 226001, China; East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Xianli Wang
- Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Lixin Sun
- East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Liang Zhu
- East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Danjing Yang
- East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Shane Gao
- East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Wenjun Zhang
- Department of Hematology, Tongji Hospital of Tongji University School of Medicine, Shanghai 200065, China
| | - Bin Ling
- The Second People's Hospital of Yunnan Province, Kunming 650021, China.
| | - Aibin Liang
- Department of Hematology, Tongji Hospital of Tongji University School of Medicine, Shanghai 200065, China.
| | - Zhengliang Gao
- Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
| | - Jun Xu
- East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
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Matos-Rodrigues GE, Martins RAP. An Eye in the Replication Stress Response: Lessons From Tissue-Specific Studies in vivo. Front Cell Dev Biol 2021; 9:731308. [PMID: 34805142 PMCID: PMC8599991 DOI: 10.3389/fcell.2021.731308] [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: 06/26/2021] [Accepted: 09/21/2021] [Indexed: 11/29/2022] Open
Abstract
Several inherited human syndromes that severely affect organogenesis and other developmental processes are caused by mutations in replication stress response (RSR) genes. Although the molecular machinery of RSR is conserved, disease-causing mutations in RSR-genes may have distinct tissue-specific outcomes, indicating that progenitor cells may differ in their responses to RSR inactivation. Therefore, understanding how different cell types respond to replication stress is crucial to uncover the mechanisms of RSR-related human syndromes. Here, we review the ocular manifestations in RSR-related human syndromes and summarize recent findings investigating the mechanisms of RSR during eye development in vivo. We highlight a remarkable heterogeneity of progenitor cells responses to RSR inactivation and discuss its implications for RSR-related human syndromes.
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Affiliation(s)
- Gabriel E Matos-Rodrigues
- Programa de Biologia Celular e do Desenvolvimento, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Rodrigo A P Martins
- Programa de Biologia Celular e do Desenvolvimento, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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45
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Meyenberg M, Ferreira da Silva J, Loizou JI. Tissue Specific DNA Repair Outcomes Shape the Landscape of Genome Editing. Front Genet 2021; 12:728520. [PMID: 34539755 PMCID: PMC8446275 DOI: 10.3389/fgene.2021.728520] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 08/05/2021] [Indexed: 12/26/2022] Open
Abstract
The use of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 has moved from bench to bedside in less than 10years, realising the vision of correcting disease through genome editing. The accuracy and safety of this approach relies on the precise control of DNA damage and repair processes to achieve the desired editing outcomes. Strategies for modulating pathway choice for repairing CRISPR-mediated DNA double-strand breaks (DSBs) have advanced the genome editing field. However, the promise of correcting genetic diseases with CRISPR-Cas9 based therapies is restrained by a lack of insight into controlling desired editing outcomes in cells of different tissue origin. Here, we review recent developments and urge for a greater understanding of tissue specific DNA repair processes of CRISPR-induced DNA breaks. We propose that integrated mapping of tissue specific DNA repair processes will fundamentally empower the implementation of precise and safe genome editing therapies for a larger variety of diseases.
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Affiliation(s)
- Mathilde Meyenberg
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
- Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Joana Ferreira da Silva
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
- Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Joanna I. Loizou
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
- Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
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46
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Therapeutic Potential of PARP Inhibitors in the Treatment of Gastrointestinal Cancers. Biomedicines 2021; 9:biomedicines9081024. [PMID: 34440228 PMCID: PMC8392860 DOI: 10.3390/biomedicines9081024] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 08/05/2021] [Accepted: 08/10/2021] [Indexed: 12/20/2022] Open
Abstract
Gastrointestinal (GI) malignancies are a major global health burden, with high mortality rates. The identification of novel therapeutic strategies is crucial to improve treatment and survival of patients. The poly (ADP-ribose) polymerase (PARP) enzymes involved in the DNA damage response (DDR) play major roles in the development, progression and treatment response of cancer, with PARP inhibitors (PARPi) currently used in the clinic for breast, ovarian, fallopian, primary peritoneal, pancreatic and prostate cancers with deficiencies in homologous recombination (HR) DNA repair. This article examines the current evidence for the role of the DDR PARP enzymes (PARP1, 2, 3 and 4) in the development, progression and treatment response of GI cancers. Furthermore, we discuss the role of HR status as a predictive biomarker of PARPi efficacy in GI cancer patients and examine the pre-clinical and clinical evidence for PARPi and cytotoxic therapy combination strategies in GI cancer. We also include an analysis of the genomic and transcriptomic landscape of the DDR PARP genes and key HR genes (BRCA1, BRCA2, ATM, RAD51, MRE11, PALB2) in GI patient tumours (n = 1744) using publicly available datasets to identify patients that may benefit from PARPi therapeutic approaches.
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47
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Ferreira da Silva J, Meyenberg M, Loizou JI. Tissue specificity of DNA repair: the CRISPR compass. Trends Genet 2021; 37:958-962. [PMID: 34392967 DOI: 10.1016/j.tig.2021.07.010] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 07/09/2021] [Accepted: 07/26/2021] [Indexed: 12/26/2022]
Abstract
CRISPR-Cas9-mediated genome editing holds great promise for the correction of pathogenic variants in humans. However, its therapeutic implementation is hampered due to unwanted editing outcomes. A better understanding of cell type- and tissue-specific DNA repair processes will ultimately enable precise control of editing outcomes for safer and effective therapies.
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Affiliation(s)
- Joana Ferreira da Silva
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria; Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria
| | - Mathilde Meyenberg
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria; Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria
| | - Joanna I Loizou
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria; Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria.
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48
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Jarysta A, Riou L, Firlej V, Lapoujade C, Kortulewski T, Barroca V, Gille AS, Dumont F, Jacques S, Letourneur F, Rosselli F, Allemand I, Fouchet P. Abnormal migration behavior linked to Rac1 signaling contributes to primordial germ cell exhaustion in Fanconi anemia pathway-deficient Fancg-/- embryos. Hum Mol Genet 2021; 31:97-110. [PMID: 34368842 PMCID: PMC8682768 DOI: 10.1093/hmg/ddab222] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 06/04/2021] [Accepted: 07/05/2021] [Indexed: 11/16/2022] Open
Abstract
Fanconi anemia (FA) is a rare human genetic disorder characterized by bone marrow failure, predisposition to cancer and developmental defects including hypogonadism. Reproductive defects leading to germ cell aplasia are the most consistent phenotypes seen in FA mouse models. We examined the role of the nuclear FA core complex gene Fancg in the development of primordial germ cells (PGCs), the embryonic precursors of adult gametes, during fetal development. PGC maintenance was severely impaired in Fancg−/− embryos. We observed a defect in the number of PGCs starting at E9.5 and a strong attrition at E11.5 and E13.5. Remarkably, we observed a mosaic pattern reflecting a portion of testicular cords devoid of PGCs in E13.5 fetal gonads. Our in vitro and in vivo data highlight a potential role of Fancg in the proliferation and in the intrinsic cell motility abilities of PGCs. The random migratory process is abnormally activated in Fancg−/− PGCs, altering the migration of cells. Increased cell death and PGC attrition observed in E11.5 Fancg−/− embryos are features consistent with delayed migration of PGCs along the migratory pathway to the genital ridges. Moreover, we show that an inhibitor of RAC1 mitigates the abnormal migratory pattern observed in Fancg−/− PGCs.
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Affiliation(s)
- Amandine Jarysta
- Université de Paris and Université Paris-Saclay, iRCM/IBFJ CEA, UMR Stabilité Génétique Cellules Souches et Radiations, Laboratoire des Cellules Souches Germinales, F-92265, Fontenay-aux-Roses, France
| | - Lydia Riou
- Université de Paris and Université Paris-Saclay, iRCM/IBFJ CEA, UMR Stabilité Génétique Cellules Souches et Radiations, Laboratoire des Cellules Souches Germinales, F-92265, Fontenay-aux-Roses, France
| | - Virginie Firlej
- Université de Paris and Université Paris-Saclay, iRCM/IBFJ CEA, UMR Stabilité Génétique Cellules Souches et Radiations, Laboratoire des Cellules Souches Germinales, F-92265, Fontenay-aux-Roses, France
| | - Clémentine Lapoujade
- Université de Paris and Université Paris-Saclay, iRCM/IBFJ CEA, UMR Stabilité Génétique Cellules Souches et Radiations, Laboratoire des Cellules Souches Germinales, F-92265, Fontenay-aux-Roses, France
| | - Thierry Kortulewski
- Université de Paris and Université Paris-Saclay, Inserm, iRCM/IBFJ CEA, UMR Stabilité Génétique Cellules Souches et Radiations, Laboratoire de RadioPathologie, F-92265, Fontenay-aux-Roses, France
| | - Vilma Barroca
- Université de Paris and Université Paris-Saclay, Inserm, iRCM/IBFJ CEA, UMR Stabilité Génétique Cellules Souches et Radiations, F-92265, Fontenay-aux-Roses, France
| | - Anne-Sophie Gille
- Université de Paris and Université Paris-Saclay, iRCM/IBFJ CEA, UMR Stabilité Génétique Cellules Souches et Radiations, Laboratoire des Cellules Souches Germinales, F-92265, Fontenay-aux-Roses, France.,Département de Génétique, Développement et Cancer. Team From Gametes to Birth, Institut Cochin, INSERM U1016, Paris, France
| | - Florent Dumont
- Université Paris Saclay, UMS IPSIT, F-92296, Châtenay-Malabry, France
| | - Sébastien Jacques
- Plate-Forme Séquençage et Génomique, Institut Cochin, Inserm U1016, Université de Paris, 22 rue Méchain, 75014 Paris, France
| | - Franck Letourneur
- Plate-Forme Séquençage et Génomique, Institut Cochin, Inserm U1016, Université de Paris, 22 rue Méchain, 75014 Paris, France
| | - Filippo Rosselli
- CNRS-UMR9019, Intégrité du Génome et Cancers, Equipe Labellisée « La Ligue Contre Le cancer », Gustave Roussy Cancer Center, Université Paris-Saclay, 94805 Villejuif, France
| | - Isabelle Allemand
- Université de Paris and Université Paris-Saclay, iRCM/IBFJ CEA, UMR Stabilité Génétique Cellules Souches et Radiations, Laboratoire des Cellules Souches Germinales, F-92265, Fontenay-aux-Roses, France
| | - Pierre Fouchet
- Université de Paris and Université Paris-Saclay, iRCM/IBFJ CEA, UMR Stabilité Génétique Cellules Souches et Radiations, Laboratoire des Cellules Souches Germinales, F-92265, Fontenay-aux-Roses, France
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49
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Lyu L, Lin TC, McCarty N. TRIM44 mediated p62 deubiquitination enhances DNA damage repair by increasing nuclear FLNA and 53BP1 expression. Oncogene 2021; 40:5116-5130. [PMID: 34211088 PMCID: PMC9744239 DOI: 10.1038/s41388-021-01890-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 05/20/2021] [Accepted: 06/04/2021] [Indexed: 12/14/2022]
Abstract
Cancer cells show increases in protein degradation pathways, including autophagy, during progression to meet the increased protein degradation demand and support cell survival. On the other hand, reduced autophagy activity during aging is associated with a reduced DNA damage response and increased genomic instability. Therefore, it is a puzzling how DNA repair can be increased in cancer cells that are resistant to chemotherapies or during progression when autophagy activity is intact or increased. We discovered that tripartite motif containing 44 (TRIM44) is a pivotal element regulating the DNA damage response in cancer cells with intact autophagy. TRIM44 deubiquitinates p62, an autophagy substrate, which leads to its oligomerization. This prevents p62 localization to the nucleus upon irradiation. Increased cytoplasmic retention of p62 by TRIM44 prevents the degradation of FLNA and 53BP1, which increases DNA damage repair. Together, our data support TRIM44 a potential therapeutic target for therapy-resistant tumor cells with intact autophagy.
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Affiliation(s)
- Lin Lyu
- Center for Stem Cell and Regenerative Disease, Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (IMM), the University of Texas-Health Science Center at Houston, Houston, Texas, 77030, USA
| | - Tsung-Chin Lin
- Center for Stem Cell and Regenerative Disease, Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (IMM), the University of Texas-Health Science Center at Houston, Houston, Texas, 77030, USA
| | - Nami McCarty
- Center for Stem Cell and Regenerative Disease, Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (IMM), the University of Texas-Health Science Center at Houston, Houston, Texas, 77030, USA.,Correspondence: Nami McCarty, Ph.D., University of Texas-Health Science Center at Houston, 1825 Pressler St., IMM-630A, Houston, TX 77030, USA, , Tel: 713-500-2495, Fax: 713-500-2424
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50
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Fang X, Huang Z, Zhai K, Huang Q, Tao W, Kim L, Wu Q, Almasan A, Yu JS, Li X, Stark GR, Rich JN, Bao S. Inhibiting DNA-PK induces glioma stem cell differentiation and sensitizes glioblastoma to radiation in mice. Sci Transl Med 2021; 13:13/600/eabc7275. [PMID: 34193614 DOI: 10.1126/scitranslmed.abc7275] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 02/23/2021] [Accepted: 06/10/2021] [Indexed: 12/11/2022]
Abstract
Glioblastoma (GBM), a lethal primary brain tumor, contains glioma stem cells (GSCs) that promote malignant progression and therapeutic resistance. SOX2 is a core transcription factor that maintains the properties of stem cells, including GSCs, but mechanisms associated with posttranslational SOX2 regulation in GSCs remain elusive. Here, we report that DNA-dependent protein kinase (DNA-PK) governs SOX2 stability through phosphorylation, resulting in GSC maintenance. Mass spectrometric analyses of SOX2-binding proteins showed that DNA-PK interacted with SOX2 in GSCs. The DNA-PK catalytic subunit (DNA-PKcs) was preferentially expressed in GSCs compared to matched non-stem cell tumor cells (NSTCs) isolated from patient-derived GBM xenografts. DNA-PKcs phosphorylated human SOX2 at S251, which stabilized SOX2 by preventing WWP2-mediated ubiquitination, thus promoting GSC maintenance. We then demonstrated that when the nuclear DNA of GSCs either in vitro or in GBM xenografts in mice was damaged by irradiation or treatment with etoposide, the DNA-PK complex dissociated from SOX2, which then interacted with WWP2, leading to SOX2 degradation and GSC differentiation. These results suggest that DNA-PKcs-mediated phosphorylation of S251 was critical for SOX2 stabilization and GSC maintenance. Pharmacological inhibition of DNA-PKcs with the DNA-PKcs inhibitor NU7441 reduced GSC tumorsphere formation in vitro and impaired growth of intracranial human GBM xenografts in mice as well as sensitized the GBM xenografts to radiotherapy. Our findings suggest that DNA-PK maintains GSCs in a stem cell state and that DNA damage triggers GSC differentiation through precise regulation of SOX2 stability, highlighting that DNA-PKcs has potential as a therapeutic target in glioblastoma.
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Affiliation(s)
- Xiaoguang Fang
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Zhi Huang
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Kui Zhai
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Qian Huang
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Weiwei Tao
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Leo Kim
- Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, CA 92037, USA.,Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Qiulian Wu
- Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, CA 92037, USA.,Division of Hematology Oncology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15261, USA
| | - Alexandru Almasan
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.,Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.,Department of Radiation Oncology, Cleveland Clinic, OH 44195, USA
| | - Jennifer S Yu
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.,Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.,Department of Radiation Oncology, Cleveland Clinic, OH 44195, USA
| | - Xiaoxia Li
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - George R Stark
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.,Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Jeremy N Rich
- Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, CA 92037, USA.,Division of Hematology Oncology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15261, USA
| | - Shideng Bao
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA. .,Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.,Center for Cancer Stem Cell Research, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
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