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1
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Huang M, Zou J, Luo B, Sun Y, Yang Z, Kong H, Long X, Sun X, Yang M, Wang X, Liu X, Zhao X. p14 ARF interacts with γ-H2AX and is involved in the DNA damage response. Biochem Biophys Res Commun 2025; 765:151847. [PMID: 40267841 DOI: 10.1016/j.bbrc.2025.151847] [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: 04/08/2025] [Accepted: 04/16/2025] [Indexed: 04/25/2025]
Abstract
p14ARF(ARF) is a tumor suppressor and functionally related to p53. Emerging evidences suggest that ARF triggers DNA damage in a p53-independent manner. However, it remains to be determined how ARF is involved in DNA damage response. Here, we report that ARF is critical in regulating the formation of DNA damage induced γ-H2AX foci. ARF binds to H2AX through its N-terminal domains to promote the phosphorylation of H2AX. The localization of ARF to the site of DNA breaks facilitates the formation of γ-H2AX foci in response to DNA damage. The knocking down of ARF significantly reduced γ-H2AX production and the number of γ-H2AX foci, leading to increased sensitivity to doxorubicin-induced cell death. Together, we propose that ARF plays a crucial role in DNA damage response through its association with H2AX and regulating γ-H2AX formation.
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Affiliation(s)
- Minyi Huang
- Clinical Research Center, Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen Key Laboratory of Bone Tissue Repair and Translational Research, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China; Laboratory of Cell Fate and Metabolic Regulation, School of Medicine, Sun Yat-sen University, Shenzhen, 518107, China
| | - Juan Zou
- Clinical Research Center, Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen Key Laboratory of Bone Tissue Repair and Translational Research, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China; Laboratory of Cell Fate and Metabolic Regulation, School of Medicine, Sun Yat-sen University, Shenzhen, 518107, China; International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen, China
| | - Biwei Luo
- Division of Hepatobiliary and Pancreas Surgery, Department of General Surgery, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China
| | - Yanxi Sun
- Laboratory of Cell Fate and Metabolic Regulation, School of Medicine, Sun Yat-sen University, Shenzhen, 518107, China
| | - Zhongzhou Yang
- Clinical Research Center, Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen Key Laboratory of Bone Tissue Repair and Translational Research, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
| | - Huimin Kong
- Clinical Research Center, Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen Key Laboratory of Bone Tissue Repair and Translational Research, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
| | - Xinxu Long
- International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen, China
| | - Xijun Sun
- International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen, China
| | - Mo Yang
- Clinical Research Center, Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen Key Laboratory of Bone Tissue Repair and Translational Research, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China.
| | - Xingwu Wang
- Laboratory of Cell Fate and Metabolic Regulation, School of Medicine, Sun Yat-sen University, Shenzhen, 518107, China.
| | - Xiangyu Liu
- International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen, China.
| | - Xiaocheng Zhao
- Clinical Research Center, Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen Key Laboratory of Bone Tissue Repair and Translational Research, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China.
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2
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Chikaishi Y, Matsuoka H, Sugihara E, Takeda M, Sumitomo M, Yamada S, Inaguma G, Omura Y, Cheong Y, Kobayashi Y, Nakauchi M, Hiro J, Masumori K, Otsuka K, Nishihara H, Suda K, Saya H, Takimoto T. Mutation Analysis of TMB-High Colorectal Cancer: Insights Into Molecular Pathways and Clinical Implications. Cancer Sci 2025; 116:1082-1093. [PMID: 39822019 PMCID: PMC11967252 DOI: 10.1111/cas.16455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 01/06/2025] [Accepted: 01/09/2025] [Indexed: 01/19/2025] Open
Abstract
Colorectal cancer (CRC) is well characterized in terms of genetic mutations and the mechanisms by which they contribute to carcinogenesis. Mutations in APC, TP53, and KRAS are common in CRC, indicating key roles for these genes in tumor development and progression. However, for certain tumors with low frequencies of these mutations that are defined by tumor location and molecular phenotypes, a carcinogenic mechanism dependent on BRAF mutations has been proposed. We here analyzed targeted sequence data linked to clinical information for CRC, focusing on tumors with a high tumor mutation burden (TMB) in order to identify the characteristics of associated mutations, their relations to clinical features, and the mechanisms of carcinogenesis in tumors lacking the major driver oncogenes. Analysis of overall mutation frequencies confirmed that APC, TP53, and KRAS mutations were the most prevalent in our cohort. Compared with other tumors, TMB-high tumors were more frequent on the right side of the colon, had lower KRAS and higher BRAF mutation frequencies as well as a higher microsatellite instability (MSI) score, and showed a greater contribution of a mutational signature associated with MSI. Ranking of variant allele frequencies to identify genes that play a role early in carcinogenesis suggested that mutations in genes related to the DNA damage response (such as ATM and POLE) and to MSI (such as MSH2 and MSH6) may precede BRAF mutations associated with activation of the serrated pathway in TMB-high tumors. Our results thus indicate that TMB-high tumors suggest that mutations of genes related to mismatch repair and the DNA damage response may contribute to activation of the serrated pathway in CRC.
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Affiliation(s)
- Yuko Chikaishi
- Department of SurgeryFujita Health UniversityToyoakeAichiJapan
| | | | - Eiji Sugihara
- Research Promotion Headquarters, Open Facility CenterFujita Health UniversityToyoakeJapan
- Oncology Innovation CenterFujita Health UniversityToyoakeAichiJapan
| | - Mayu Takeda
- Faculty of Health and Medical SciencesAichi Syukutoku UniversityNagakuteAichiJapan
| | - Makoto Sumitomo
- Oncology Innovation CenterFujita Health UniversityToyoakeAichiJapan
| | - Seiji Yamada
- Oncology Innovation CenterFujita Health UniversityToyoakeAichiJapan
| | - Gaku Inaguma
- Department of SurgeryFujita Health UniversityToyoakeAichiJapan
| | - Yusuke Omura
- Department of SurgeryFujita Health UniversityToyoakeAichiJapan
| | | | | | - Masaya Nakauchi
- Department of Advanced Robotic and Endoscopic SurgeryFujita Health UniversityToyoakeAichiJapan
| | - Junichiro Hiro
- Department of SurgeryFujita Health UniversityToyoakeAichiJapan
| | - Koji Masumori
- Department of SurgeryFujita Health UniversityToyoakeAichiJapan
| | - Koki Otsuka
- Department of Advanced Robotic and Endoscopic SurgeryFujita Health UniversityToyoakeAichiJapan
| | - Hiroshi Nishihara
- Center for Cancer GenomicsKeio University School of MedicineTokyoJapan
| | - Koichi Suda
- Department of SurgeryFujita Health UniversityToyoakeAichiJapan
- Collaborative Laboratory for Research and Development in Advanced Surgical IntelligenceFujita Health UniversityToyoakeAichiJapan
| | - Hideyuki Saya
- Oncology Innovation CenterFujita Health UniversityToyoakeAichiJapan
| | - Tetsuya Takimoto
- Oncology Innovation CenterFujita Health UniversityToyoakeAichiJapan
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3
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Muta Y, Nakanishi Y. Mouse colorectal cancer organoids: Lessons from syngeneic and orthotopic transplantation systems. Eur J Cell Biol 2025; 104:151478. [PMID: 39919450 DOI: 10.1016/j.ejcb.2025.151478] [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: 08/19/2024] [Revised: 01/01/2025] [Accepted: 02/04/2025] [Indexed: 02/09/2025] Open
Abstract
Colorectal cancer (CRC) organoids provide more accurate and tissue-relevant models compared to conventional two-dimensional cultured cell cultures. Mouse CRC organoids, in particular, offer unique advantages over their human counterparts, as they can be transplanted into immunocompetent mice. These syngeneic transplantation models create a robust system for studying cancer biology in the immunocompetent tumor microenvironment (TME). This article discusses the development and applications of these organoid systems, emphasizing their capacity to faithfully recapitulate in vivo tumor progression, metastasis, and the immune landscape.
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Affiliation(s)
- Yu Muta
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yuki Nakanishi
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
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Kinoshita H, Martinez-Ordoñez A, Cid-Diaz T, Han Q, Duran A, Muta Y, Zhang X, Linares JF, Nakanishi Y, Kasashima H, Yashiro M, Maeda K, Albaladejo-Gonzalez A, Torres-Moreno D, García-Solano J, Conesa-Zamora P, Inghirami G, Diaz-Meco MT, Moscat J. Epithelial aPKC deficiency leads to stem cell loss preceding metaplasia in colorectal cancer initiation. Dev Cell 2024; 59:1972-1987.e8. [PMID: 38815584 PMCID: PMC11303105 DOI: 10.1016/j.devcel.2024.05.001] [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: 08/01/2023] [Revised: 12/19/2023] [Accepted: 05/03/2024] [Indexed: 06/01/2024]
Abstract
The early mechanisms of spontaneous tumor initiation that precede malignancy are largely unknown. We show that reduced aPKC levels correlate with stem cell loss and the induction of revival and metaplastic programs in serrated- and conventional-initiated premalignant lesions, which is perpetuated in colorectal cancers (CRCs). Acute inactivation of PKCλ/ι in vivo and in mouse organoids is sufficient to stimulate JNK in non-transformed intestinal epithelial cells (IECs), which promotes cell death and the rapid loss of the intestinal stem cells (ISCs), including those that are LGR5+. This is followed by the accumulation of revival stem cells (RSCs) at the bottom of the crypt and fetal-metaplastic cells (FMCs) at the top, creating two spatiotemporally distinct cell populations that depend on JNK-induced AP-1 and YAP. These cell lineage changes are maintained during cancer initiation and progression and determine the aggressive phenotype of human CRC, irrespective of their serrated or conventional origin.
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Affiliation(s)
- Hiroto Kinoshita
- Department of Pathology and Laboratory Medicine and Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA
| | - Anxo Martinez-Ordoñez
- Department of Pathology and Laboratory Medicine and Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA
| | - Tania Cid-Diaz
- Department of Pathology and Laboratory Medicine and Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA
| | - Qixiu Han
- Department of Pathology and Laboratory Medicine and Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA
| | - Angeles Duran
- Department of Pathology and Laboratory Medicine and Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA
| | - Yu Muta
- Department of Pathology and Laboratory Medicine and Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA; Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Xiao Zhang
- Department of Pathology and Laboratory Medicine and Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA
| | - Juan F Linares
- Department of Pathology and Laboratory Medicine and Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA
| | - Yuki Nakanishi
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hiroaki Kasashima
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka city 545-8585, Japan
| | - Masakazu Yashiro
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka city 545-8585, Japan
| | - Kiyoshi Maeda
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka city 545-8585, Japan
| | - Ana Albaladejo-Gonzalez
- Department of Histology and Pathology, Faculty of Life Sciences, Universidad Católica de Murcia (UCAM), 30107 Murcia, Spain; Department of Pathology, Santa Lucía General University Hospital (HGUSL), Calle Mezquita sn, 30202 Cartagena, Spain
| | - Daniel Torres-Moreno
- Department of Histology and Pathology, Faculty of Life Sciences, Universidad Católica de Murcia (UCAM), 30107 Murcia, Spain; Department of Clinical Analysis, Santa Lucía General University Hospital (HGUSL), Calle Mezquita sn, 30202 Cartagena, Spain
| | - José García-Solano
- Department of Histology and Pathology, Faculty of Life Sciences, Universidad Católica de Murcia (UCAM), 30107 Murcia, Spain; Department of Pathology, Santa Lucía General University Hospital (HGUSL), Calle Mezquita sn, 30202 Cartagena, Spain
| | - Pablo Conesa-Zamora
- Department of Histology and Pathology, Faculty of Life Sciences, Universidad Católica de Murcia (UCAM), 30107 Murcia, Spain; Department of Clinical Analysis, Santa Lucía General University Hospital (HGUSL), Calle Mezquita sn, 30202 Cartagena, Spain
| | - Giorgio Inghirami
- Department of Pathology and Laboratory Medicine and Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA
| | - Maria T Diaz-Meco
- Department of Pathology and Laboratory Medicine and Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA.
| | - Jorge Moscat
- Department of Pathology and Laboratory Medicine and Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA.
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Xiao R, Hu S, Du X, Wang Y, Fang K, Zhu Y, Lou N, Yuan C, Yang J. Revolutionizing Senescence Detection: Advancements from Traditional Methods to Cutting-Edge Techniques. Aging Dis 2024; 16:1285-1301. [PMID: 39012669 PMCID: PMC12096929 DOI: 10.14336/ad.202.0565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Accepted: 07/01/2024] [Indexed: 07/17/2024] Open
Abstract
The accumulation of senescent cells is an important factor in the complex progression of aging, with significant implications for the development of numerous diseases. Thus, understanding the fundamental mechanisms of senescence is paramount for advancing preventive and therapeutic approaches to age-related conditions. Important to this pursuit is the precise identification and examination of senescent cells, contingent upon the recognition of specific biomarkers. Historically, detection methods relied on assessing molecular protein and mRNA levels and various staining techniques. While these conventional approaches have contributed substantially to the field, they possess limitations in capturing the dynamic evolution of cellular aging in real time. The emergence of novel technologies has led to a paradigm shift in senescence research. Gene-edited mouse models and the application of advanced probes have revolutionized our ability to detect senescent cells. These cutting-edge methodologies provide a more detailed and accurate means of dynamically monitoring, characterizing and potentially eliminating senescent cells, thus enhancing our understanding of the complex mechanisms of aging. This review comprehensively explores both traditional and innovative senescent cell detection methods, elucidating their advantages, limitations and implications for future investigations and could serve as a comprehensive guide and catalyst for further advancements in the understanding of aging and associated pathologies.
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Affiliation(s)
| | | | - Xiaohui Du
- Department of Basic Medicine, School of Medicine, Hangzhou City University, Hangzhou, Zhejiang, China
| | - Yiwen Wang
- Department of Basic Medicine, School of Medicine, Hangzhou City University, Hangzhou, Zhejiang, China
| | - Ke Fang
- Department of Basic Medicine, School of Medicine, Hangzhou City University, Hangzhou, Zhejiang, China
| | - Yibin Zhu
- Department of Basic Medicine, School of Medicine, Hangzhou City University, Hangzhou, Zhejiang, China
| | - Nanbin Lou
- Department of Basic Medicine, School of Medicine, Hangzhou City University, Hangzhou, Zhejiang, China
| | - Chunhui Yuan
- Department of Basic Medicine, School of Medicine, Hangzhou City University, Hangzhou, Zhejiang, China
| | - Jing Yang
- Department of Basic Medicine, School of Medicine, Hangzhou City University, Hangzhou, Zhejiang, China
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Gao C, Ge H, Kuan SF, Cai C, Lu X, Esni F, Schoen RE, Wang JH, Chu E, Hu J. FAK loss reduces BRAF V600E-induced ERK phosphorylation to promote intestinal stemness and cecal tumor formation. eLife 2024; 13:RP94605. [PMID: 38921956 PMCID: PMC11208045 DOI: 10.7554/elife.94605] [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] [Indexed: 06/27/2024] Open
Abstract
BRAFV600E mutation is a driver mutation in the serrated pathway to colorectal cancers. BRAFV600E drives tumorigenesis through constitutive downstream extracellular signal-regulated kinase (ERK) activation, but high-intensity ERK activation can also trigger tumor suppression. Whether and how oncogenic ERK signaling can be intrinsically adjusted to a 'just-right' level optimal for tumorigenesis remains undetermined. In this study, we found that FAK (Focal adhesion kinase) expression was reduced in BRAFV600E-mutant adenomas/polyps in mice and patients. In Vil1-Cre;BRAFLSL-V600E/+;Ptk2fl/fl mice, Fak deletion maximized BRAFV600E's oncogenic activity and increased cecal tumor incidence to 100%. Mechanistically, our results showed that Fak loss, without jeopardizing BRAFV600E-induced ERK pathway transcriptional output, reduced EGFR (epidermal growth factor receptor)-dependent ERK phosphorylation. Reduction in ERK phosphorylation increased the level of Lgr4, promoting intestinal stemness and cecal tumor formation. Our findings show that a 'just-right' ERK signaling optimal for BRAFV600E-induced cecal tumor formation can be achieved via Fak loss-mediated downregulation of ERK phosphorylation.
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Affiliation(s)
- Chenxi Gao
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of MedicinePittsburghUnited States
| | - Huaibin Ge
- UPMC Hillman Cancer Center, Division of Hematology and Oncology, Department of Medicine, University of PittsburghPittsburghUnited States
| | - Shih-Fan Kuan
- Department of Pathology, University of Pittsburgh School of MedicinePittsburghUnited States
| | - Chunhui Cai
- Department of Biomedical Informatics, University of PittsburghPittsburghUnited States
| | - Xinghua Lu
- Department of Biomedical Informatics, University of PittsburghPittsburghUnited States
| | - Farzad Esni
- Department of Surgery, University of Pittsburgh School of MedicinePittsburghUnited States
| | - Robert E Schoen
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of MedicinePittsburghUnited States
| | - Jing H Wang
- UPMC Hillman Cancer Center, Division of Hematology and Oncology, Department of Medicine, University of PittsburghPittsburghUnited States
| | - Edward Chu
- UPMC Hillman Cancer Center, Division of Hematology and Oncology, Department of Medicine, University of PittsburghPittsburghUnited States
| | - Jing Hu
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of MedicinePittsburghUnited States
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7
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Hohmann M, Brunner V, Johannes W, Schum D, Carroll LM, Liu T, Sasaki D, Bosch J, Clavel T, Sieber SA, Zeller G, Tschurtschenthaler M, Janßen KP, Gulder TAM. Bacillamide D produced by Bacillus cereus from the mouse intestinal bacterial collection (miBC) is a potent cytotoxin in vitro. Commun Biol 2024; 7:655. [PMID: 38806706 PMCID: PMC11133360 DOI: 10.1038/s42003-024-06208-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Accepted: 04/17/2024] [Indexed: 05/30/2024] Open
Abstract
The gut microbiota influences human health and the development of chronic diseases. However, our understanding of potentially protective or harmful microbe-host interactions at the molecular level is still in its infancy. To gain further insights into the hidden gut metabolome and its impact, we identified a cryptic non-ribosomal peptide BGC in the genome of Bacillus cereus DSM 28590 from the mouse intestine ( www.dsmz.de/miBC ), which was predicted to encode a thiazol(in)e substructure. Cloning and heterologous expression of this BGC revealed that it produces bacillamide D. In-depth functional evaluation showed potent cytotoxicity and inhibition of cell migration using the human cell lines HCT116 and HEK293, which was validated using primary mouse organoids. This work establishes the bacillamides as selective cytotoxins from a bacterial gut isolate that affect mammalian cells. Our targeted structure-function-predictive approach is demonstrated to be a streamlined method to discover deleterious gut microbial metabolites with potential effects on human health.
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Affiliation(s)
- Maximilian Hohmann
- Chair of Technical Biochemistry, Technical University of Dresden, Bergstraße 66, 01069, Dresden, Germany
| | - Valentina Brunner
- Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine and Health, Technical University of Munich, 81675, Munich, Germany
- Center for Translational Cancer Research (TranslaTUM), Klinikum rechts der Isar, School of Medicine and Health, Technical University of Munich, 81675, Munich, Germany
- Division of Translational Cancer Research German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120, Heidelberg, Germany
| | - Widya Johannes
- Department of Surgery, Klinikum rechts der Isar, School of Medicine and Health, Technical University of Munich, 81675, Munich, Germany
| | - Dominik Schum
- Department of Bioscience, Center for Functional Protein Assemblies, Technical University of Munich, 85748, Garching bei München, Germany
| | - Laura M Carroll
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, 61997, Heidelberg, Germany
| | - Tianzhe Liu
- Chair of Technical Biochemistry, Technical University of Dresden, Bergstraße 66, 01069, Dresden, Germany
| | - Daisuke Sasaki
- Department of Surgery, Klinikum rechts der Isar, School of Medicine and Health, Technical University of Munich, 81675, Munich, Germany
- Research and Development Headquarters, Nitto Boseki Co., Ltd., 102-8489, Tokyo, Japan
| | - Johanna Bosch
- Functional Microbiome Research Group, Institute of Medical Microbiology, University Hospital of RWTH Aachen, 52074, Aachen, Germany
| | - Thomas Clavel
- Functional Microbiome Research Group, Institute of Medical Microbiology, University Hospital of RWTH Aachen, 52074, Aachen, Germany
| | - Stephan A Sieber
- Department of Bioscience, Center for Functional Protein Assemblies, Technical University of Munich, 85748, Garching bei München, Germany
| | - Georg Zeller
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, 61997, Heidelberg, Germany
| | - Markus Tschurtschenthaler
- Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine and Health, Technical University of Munich, 81675, Munich, Germany.
- Center for Translational Cancer Research (TranslaTUM), Klinikum rechts der Isar, School of Medicine and Health, Technical University of Munich, 81675, Munich, Germany.
- Division of Translational Cancer Research German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120, Heidelberg, Germany.
| | - Klaus-Peter Janßen
- Department of Surgery, Klinikum rechts der Isar, School of Medicine and Health, Technical University of Munich, 81675, Munich, Germany.
| | - Tobias A M Gulder
- Chair of Technical Biochemistry, Technical University of Dresden, Bergstraße 66, 01069, Dresden, Germany.
- Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Department of Natural Product Biotechnology, Helmholtz Centre for Infection Research (HZI) and Department of Pharmacy at Saarland University, Campus E8.1, 66123, Saarbrücken, Germany.
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8
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Silva AO, Bitencourt TC, Vargas JE, Fraga LR, Filippi-Chiela E. Modulation of tumor plasticity by senescent cells: Deciphering basic mechanisms and survival pathways to unravel therapeutic options. Genet Mol Biol 2024; 47Suppl 1:e20230311. [PMID: 38805699 PMCID: PMC11132560 DOI: 10.1590/1678-4685-gmb-2023-0311] [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: 11/02/2023] [Accepted: 03/21/2024] [Indexed: 05/30/2024] Open
Abstract
Senescence is a cellular state in which the cell loses its proliferative capacity, often irreversibly. Physiologically, it occurs due to a limited capacity of cell division associated with telomere shortening, the so-called replicative senescence. It can also be induced early due to DNA damage, oncogenic activation, oxidative stress, or damage to other cellular components (collectively named induced senescence). Tumor cells acquire the ability to bypass replicative senescence, thus ensuring the replicative immortality, a hallmark of cancer. Many anti-cancer therapies, however, can lead tumor cells to induced senescence. Initially, this response leads to a slowdown in tumor growth. However, the longstanding accumulation of senescent cells (SnCs) in tumors can promote neoplastic progression due to the enrichment of numerous molecules and extracellular vesicles that constitutes the senescence-associated secretory phenotype (SASP). Among other effects, SASP can potentiate or unlock the tumor plasticity and phenotypic transitions, another hallmark of cancer. This review discusses how SnCs can fuel mechanisms that underlie cancer plasticity, like cell differentiation, stemness, reprogramming, and epithelial-mesenchymal transition. We also discuss the main molecular mechanisms that make SnCs resistant to cell death, and potential strategies to target SnCs. At the end, we raise open questions and clinically relevant perspectives in the field.
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Affiliation(s)
- Andrew Oliveira Silva
- Faculdade Estácio, Porto Alegre, RS, Brazil
- Centro de Pesquisa Experimental, Hospital de Clínicas de Porto
Alegre, Porto Alegre, RS, Brazil
| | - Thais Cardoso Bitencourt
- Centro de Pesquisa Experimental, Hospital de Clínicas de Porto
Alegre, Porto Alegre, RS, Brazil
- Universidade Federal do Rio Grande do Sul, Programa de Pós-Graduação
em Biologia Celular e Molecular, Porto Alegre, RS, Brazil
| | - Jose Eduardo Vargas
- Universidade Federal do Paraná, Departamento de Biologia Celular,
Curitiba, PR, Brazil
| | - Lucas Rosa Fraga
- Centro de Pesquisa Experimental, Hospital de Clínicas de Porto
Alegre, Porto Alegre, RS, Brazil
- Universidade Federal do Rio Grande do Sul, Departamento de Ciências
Morfológicas, Porto Alegre, RS, Brazil
- Universidade Federal do Rio Grande do Sul, Programa de Pós-Graduação
em Medicina: Ciências Médicas, Porto Alegre, RS, Brazil
| | - Eduardo Filippi-Chiela
- Centro de Pesquisa Experimental, Hospital de Clínicas de Porto
Alegre, Porto Alegre, RS, Brazil
- Universidade Federal do Rio Grande do Sul, Departamento de Ciências
Morfológicas, Porto Alegre, RS, Brazil
- Universidade Federal do Rio Grande do Sul, Centro de Biotecnologia,
Porto Alegre, RS, Brazil
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9
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Iida N, Muranaka Y, Park JW, Sekine S, Copeland NG, Jenkins NA, Shiraishi Y, Oshima M, Takeda H. Sleeping Beauty transposon mutagenesis in mouse intestinal organoids identifies genes involved in tumor progression and metastasis. Cancer Gene Ther 2024; 31:527-536. [PMID: 38177308 DOI: 10.1038/s41417-023-00723-x] [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: 10/12/2023] [Revised: 12/14/2023] [Accepted: 12/19/2023] [Indexed: 01/06/2024]
Abstract
To identify genes important for colorectal cancer (CRC) development and metastasis, we established a new metastatic mouse organoid model using Sleeping Beauty (SB) transposon mutagenesis. Intestinal organoids derived from mice carrying actively mobilizing SB transposons, an activating KrasG12D, and an inactivating ApcΔ716 allele, were transplanted to immunodeficient mice. While 66.7% of mice developed primary tumors, 7.6% also developed metastatic tumors. Analysis of SB insertion sites in tumors identified numerous candidate cancer genes (CCGs) identified previously in intestinal SB screens performed in vivo, in addition to new CCGs, such as Slit2 and Atxn1. Metastatic tumors from the same mouse were clonally related to each other and to primary tumors, as evidenced by the transposon insertion site. To provide functional validation, we knocked out Slit2, Atxn1, and Cdkn2a in mouse tumor organoids and transplanted to mice. Tumor development was promoted when these gene were knocked out, demonstrating that these are potent tumor suppressors. Cdkn2a knockout cells also metastasized to the liver in 100% of the mice, demonstrating that Cdkn2a loss confers metastatic ability. Our organoid model thus provides a new approach that can be used to understand the evolutionary forces driving CRC metastasis and a rich resource to uncover CCGs promoting CRC.
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Affiliation(s)
- Naoko Iida
- Division of Genome Analysis Platform Development, National Cancer Center Research Institute, Tokyo, Japan
| | - Yukari Muranaka
- Laboratory of Molecular Genetics, National Cancer Center Research Institute, Tokyo, Japan
| | - Jun Won Park
- Division of Biomedical Convergence, College of Biomedical Science, Kang-won National University, Chuncheon-si, Republic of Korea
| | - Shigeki Sekine
- Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan
| | - Neal G Copeland
- Genetics Department, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Nancy A Jenkins
- Genetics Department, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yuichi Shiraishi
- Division of Genome Analysis Platform Development, National Cancer Center Research Institute, Tokyo, Japan
| | - Masanobu Oshima
- Division of Genetics, Cancer Research Institute, Kanazawa University, Ishikawa, Japan
- Nano-Life Science Institute, Kanazawa University, Ishikawa, Japan
| | - Haruna Takeda
- Laboratory of Molecular Genetics, National Cancer Center Research Institute, Tokyo, Japan.
- Cancer genes and genomes unit, Cancer Research Institute, Kanazawa University, Ishikawa, Japan.
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10
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Felchle H, Brunner V, Groll T, Walther CN, Nefzger SM, Zaurito AE, Silva MG, Gissibl J, Topping GJ, Lansink Rotgerink L, Saur D, Steiger K, Combs SE, Tschurtschenthaler M, Fischer JC. Novel Tumor Organoid-Based Mouse Model to Study Image Guided Radiation Therapy of Rectal Cancer After Noninvasive and Precise Endoscopic Implantation. Int J Radiat Oncol Biol Phys 2024; 118:1094-1104. [PMID: 37875245 DOI: 10.1016/j.ijrobp.2023.10.008] [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: 06/23/2023] [Accepted: 10/08/2023] [Indexed: 10/26/2023]
Abstract
PURPOSE Preoperative (neoadjuvant) radiation therapy (RT) is an essential part of multimodal rectal cancer therapy. Recently, total neoadjuvant therapy (TNT), which combines simultaneous radiochemotherapy with additional courses of chemotherapy, has emerged as an effective approach. TNT achieves a pathologic complete remission in approximately 30% of resected patients, opening avenues for treatment strategies that avoid radical organ resection. Furthermore, recent studies have demonstrated that anti-programmed cell death protein 1 immunotherapy can induce clinical complete responses in patients with specific genetic alterations. There is significant potential to enhance outcomes through intensifying, personalizing, and de-escalating treatment approaches. However, the heterogeneous response rates to RT or TNT and strategies to sensitize patients without specific genetic changes to immunotherapy remain poorly understood. METHODS AND MATERIALS We developed a novel orthotopic mouse model of rectal cancer based on precisely defined endoscopic injections of tumor organoids that reflect tumor heterogeneity. Subsequently, we employed endoscopic- and computed tomography-guided RT and validated rectal tumor growth and response rates to therapy using small-animal magnetic resonance imaging and endoscopic follow-up. RESULTS Rectal tumor formation was successfully induced in all mice after 2 organoid injections. Clinically relevant RT regimens with 5 × 5 Gy significantly delayed clinical signs of tumor progression and significantly improved survival. Consistent with human disease, rectal tumor progression correlated with the development of liver and lung metastases. Notably, long-term survivors after RT showed no evidence of tumor recurrence, as demonstrated by in vivo radiologic tumor staging and histopathologic examination. CONCLUSIONS Our novel mouse model combines orthotopic tumor growth via noninvasive and precise rectal organoid injection and small-animal RT. This model holds significant promise for investigating the effect of tumor cell-intrinsic aspects, genetic alterations of the host, and exogenous factors (eg, nutrition or microbiota) on RT outcomes. Furthermore, it allows for the exploration of combination therapies involving chemotherapy, immunotherapy, or novel targeted therapies.
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Affiliation(s)
- Hannah Felchle
- Department of Radiation Oncology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Valentina Brunner
- Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany; Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany
| | - Tanja Groll
- Comparative Experimental Pathology, School of Medicine, Technical University of Munich, Munich, Germany; Institute of Pathology, School of Medicine, Technical University of Munich, Munich, Germany
| | - Caroline N Walther
- Department of Radiation Oncology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Sophie M Nefzger
- Department of Radiation Oncology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Antonio E Zaurito
- Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany; Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany
| | - Miguel G Silva
- Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany; Institute of Molecular Oncology and Functional Genomics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Julia Gissibl
- Department of Radiation Oncology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Geoffrey J Topping
- Department of Nuclear Medicine, School of Medicine, Technical University of Munich, Munich, Germany
| | - Laura Lansink Rotgerink
- Department of Radiation Oncology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Dieter Saur
- Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany; Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany; German Cancer Consortium (DKTK), Partner-site Munich and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Katja Steiger
- Comparative Experimental Pathology, School of Medicine, Technical University of Munich, Munich, Germany; Institute of Pathology, School of Medicine, Technical University of Munich, Munich, Germany; German Cancer Consortium (DKTK), Partner-site Munich and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Stephanie E Combs
- Department of Radiation Oncology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany; German Cancer Consortium (DKTK), Partner-site Munich and German Cancer Research Center (DKFZ), Heidelberg, Germany; Helmholtz Zentrum München, Institute of Radiation Medicine, Neuherberg, Germany
| | - Markus Tschurtschenthaler
- Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany; Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany; German Cancer Consortium (DKTK), Partner-site Munich and German Cancer Research Center (DKFZ), Heidelberg, Germany.
| | - Julius C Fischer
- Department of Radiation Oncology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.
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11
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Jamalzadeh S, Dai J, Lavikka K, Li Y, Jiang J, Huhtinen K, Virtanen A, Oikkonen J, Hietanen S, Hynninen J, Vähärautio A, Häkkinen A, Hautaniemi S. Genome-wide quantification of copy-number aberration impact on gene expression in ovarian high-grade serous carcinoma. BMC Cancer 2024; 24:173. [PMID: 38317080 PMCID: PMC10840274 DOI: 10.1186/s12885-024-11895-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Accepted: 01/17/2024] [Indexed: 02/07/2024] Open
Abstract
Copy-number alterations (CNAs) are a hallmark of cancer and can regulate cancer cell states via altered gene expression values. Herein, we have developed a copy-number impact (CNI) analysis method that quantifies the degree to which a gene expression value is impacted by CNAs and leveraged this analysis at the pathway level. Our results show that a high CNA is not necessarily reflected at the gene expression level, and our method is capable of detecting genes and pathways whose activity is strongly influenced by CNAs. Furthermore, the CNI analysis enables unbiased categorization of CNA categories, such as deletions and amplifications. We identified six CNI-driven pathways associated with poor treatment response in ovarian high-grade serous carcinoma (HGSC), which we found to be the most CNA-driven cancer across 14 cancer types. The key driver in most of these pathways was amplified wild-type KRAS, which we validated functionally using CRISPR modulation. Our results suggest that wild-type KRAS amplification is a driver of chemotherapy resistance in HGSC and may serve as a potential treatment target.
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Affiliation(s)
- Sanaz Jamalzadeh
- Research Program in Systems Oncology, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Jun Dai
- Research Program in Systems Oncology, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Kari Lavikka
- Research Program in Systems Oncology, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Yilin Li
- Research Program in Systems Oncology, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Jing Jiang
- Research Program in Systems Oncology, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Kaisa Huhtinen
- Research Program in Systems Oncology, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Institute of Biomedicine and FICAN West Cancer Centre, University of Turku and Turku University Hospital, Turku, Finland
| | - Anni Virtanen
- Department of Pathology, University of Helsinki and HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland
| | - Jaana Oikkonen
- Research Program in Systems Oncology, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Sakari Hietanen
- Department of Obstetrics and Gynecology, University of Turku and Turku University Hospital, Turku, Finland
| | - Johanna Hynninen
- Department of Obstetrics and Gynecology, University of Turku and Turku University Hospital, Turku, Finland
| | - Anna Vähärautio
- Research Program in Systems Oncology, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Foundation for the Finnish Cancer Institute, Helsinki, Finland
| | - Antti Häkkinen
- Research Program in Systems Oncology, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
- Computational Health Informatics Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
| | - Sampsa Hautaniemi
- Research Program in Systems Oncology, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
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12
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Gao C, Ge H, Kuan SF, Cai C, Lu X, Esni F, Schoen R, Wang J, Chu E, Hu J. FAK loss reduces BRAF V600E-induced ERK phosphorylation to promote intestinal stemness and cecal tumor formation. RESEARCH SQUARE 2024:rs.3.rs-2531119. [PMID: 36778401 PMCID: PMC9915899 DOI: 10.21203/rs.3.rs-2531119/v2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 07/04/2024]
Abstract
BRAF V600E mutation is a driver mutation in the serrated pathway to colorectal cancers. BRAFV600E drives tumorigenesis through constitutive downstream extracellular signal-regulated kinase (ERK) activation, but high-intensity ERK activation can also trigger tumor suppression. Whether and how oncogenic ERK signaling can be intrinsically adjusted to a "just-right" level optimal for tumorigenesis remains undetermined. In this study, we found that FAK (Focal adhesion kinase) expression was reduced in BRAFV600E-mutant adenomas/polyps in mice and patients. In Vill-Cre;BRAFV600E/+;Fakfl/fl mice, Fak deletion maximized BRAFV600E's oncogenic activity and increased cecal tumor incidence to 100%. Mechanistically, our results showed that Fak loss, without jeopardizing BRAFV600E-induced ERK pathway transcriptional output, reduced EGFR (epidermal growth factor receptor)-dependent ERK phosphorylation. Reduction in ERK phosphorylation increased the level of Lgr4, promoting intestinal stemness and cecal tumor formation. Our findings show that a "just-right" ERK signaling optimal for BRAFV600E-induced cecal tumor formation can be achieved via Fak loss-mediated downregulation of ERK phosphorylation.
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Affiliation(s)
| | | | | | | | | | | | | | - Jing Wang
- UPMC Hillman Cancer Center/University of Pittsburgh
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13
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Trembath HE, Yeh JJ, Lopez NE. Gastrointestinal Malignancy: Genetic Implications to Clinical Applications. Cancer Treat Res 2024; 192:305-418. [PMID: 39212927 DOI: 10.1007/978-3-031-61238-1_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Advances in molecular genetics have revolutionized our understanding of the pathogenesis, progression, and therapeutic options for treating gastrointestinal (GI) cancers. This chapter provides a comprehensive overview of the molecular landscape of GI cancers, focusing on key genetic alterations implicated in tumorigenesis across various anatomical sites including GIST, colon and rectum, and pancreas. Emphasis is placed on critical oncogenic pathways, such as mutations in tumor suppressor genes, oncogenes, chromosomal instability, microsatellite instability, and epigenetic modifications. The role of molecular biomarkers in predicting prognosis, guiding treatment decisions, and monitoring therapeutic response is discussed, highlighting the integration of genomic profiling into clinical practice. Finally, we address the evolving landscape of precision oncology in GI cancers, considering targeted therapies and immunotherapies.
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Affiliation(s)
- Hannah E Trembath
- Division of Colon and Rectal Surgery, Department of Surgery, University of California San Diego, 4303 La Jolla Village Drive Suite 2110, San Diego, CA, 92122, USA
- Division of Surgical Oncology, Department of Surgery, University of North Carolina, 170 Manning Drive, CB#7213, 1150 Physician's Office Building, Chapel Hill, NC, 27599-7213, USA
| | - Jen Jen Yeh
- Division of Colon and Rectal Surgery, Department of Surgery, University of California San Diego, 4303 La Jolla Village Drive Suite 2110, San Diego, CA, 92122, USA
- Division of Surgical Oncology, Department of Surgery, University of North Carolina, 170 Manning Drive, CB#7213, 1150 Physician's Office Building, Chapel Hill, NC, 27599-7213, USA
| | - Nicole E Lopez
- Division of Colon and Rectal Surgery, Department of Surgery, University of California San Diego, 4303 La Jolla Village Drive Suite 2110, San Diego, CA, 92122, USA.
- Division of Surgical Oncology, Department of Surgery, University of North Carolina, 170 Manning Drive, CB#7213, 1150 Physician's Office Building, Chapel Hill, NC, 27599-7213, USA.
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14
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Aiderus A, Barker N, Tergaonkar V. Serrated colorectal cancer: preclinical models and molecular pathways. Trends Cancer 2024; 10:76-91. [PMID: 37880007 DOI: 10.1016/j.trecan.2023.09.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 09/26/2023] [Accepted: 09/28/2023] [Indexed: 10/27/2023]
Abstract
Serrated lesions are histologically heterogeneous, and detection can be challenging as these lesions have subtle features that may be missed by endoscopy. Furthermore, while approximately 30% of colorectal cancers (CRCs) arise from serrated lesions, only 8-10% of invasive serrated CRCs exhibit serrated morphology at presentation, suggesting potential loss of apparent characteristics with increased malignancy. Thus, understanding the genetic basis driving serrated CRC initiation and progression is critical to improve diagnosis and identify therapeutic biomarkers and targets to guide disease management. This review discusses the preclinical models of serrated CRCs reported to date and how these systems have been used to provide mechanistic insights into tumor initiation, progression, and novel treatment targets.
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Affiliation(s)
- Aziz Aiderus
- Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Republic of Singapore.
| | - Nick Barker
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), 2 Medical Drive, MD9, Singapore 117593, Republic of Singapore; Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Republic of Singapore
| | - Vinay Tergaonkar
- Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Republic of Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (NUS), 8 Medical Drive, MD7, Singapore 117596, Republic of Singapore
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15
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Muta Y, Linares JF, Martinez-Ordoñez A, Duran A, Cid-Diaz T, Kinoshita H, Zhang X, Han Q, Nakanishi Y, Nakanishi N, Cordes T, Arora GK, Ruiz-Martinez M, Reina-Campos M, Kasashima H, Yashiro M, Maeda K, Albaladejo-Gonzalez A, Torres-Moreno D, García-Solano J, Conesa-Zamora P, Inghirami G, Metallo CM, Osborne TF, Diaz-Meco MT, Moscat J. Enhanced SREBP2-driven cholesterol biosynthesis by PKCλ/ι deficiency in intestinal epithelial cells promotes aggressive serrated tumorigenesis. Nat Commun 2023; 14:8075. [PMID: 38092754 PMCID: PMC10719313 DOI: 10.1038/s41467-023-43690-5] [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: 08/25/2023] [Accepted: 11/16/2023] [Indexed: 12/17/2023] Open
Abstract
The metabolic and signaling pathways regulating aggressive mesenchymal colorectal cancer (CRC) initiation and progression through the serrated route are largely unknown. Although relatively well characterized as BRAF mutant cancers, their poor response to current targeted therapy, difficult preneoplastic detection, and challenging endoscopic resection make the identification of their metabolic requirements a priority. Here, we demonstrate that the phosphorylation of SCAP by the atypical PKC (aPKC), PKCλ/ι promotes its degradation and inhibits the processing and activation of SREBP2, the master regulator of cholesterol biosynthesis. We show that the upregulation of SREBP2 and cholesterol by reduced aPKC levels is essential for controlling metaplasia and generating the most aggressive cell subpopulation in serrated tumors in mice and humans. Since these alterations are also detected prior to neoplastic transformation, together with the sensitivity of these tumors to cholesterol metabolism inhibitors, our data indicate that targeting cholesterol biosynthesis is a potential mechanism for serrated chemoprevention.
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Affiliation(s)
- Yu Muta
- Department of Pathology and Laboratory Medicine and Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Juan F Linares
- Department of Pathology and Laboratory Medicine and Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Anxo Martinez-Ordoñez
- Department of Pathology and Laboratory Medicine and Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Angeles Duran
- Department of Pathology and Laboratory Medicine and Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Tania Cid-Diaz
- Department of Pathology and Laboratory Medicine and Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Hiroto Kinoshita
- Department of Pathology and Laboratory Medicine and Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Xiao Zhang
- Department of Pathology and Laboratory Medicine and Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Qixiu Han
- Department of Pathology and Laboratory Medicine and Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Yuki Nakanishi
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Naoko Nakanishi
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Thekla Cordes
- Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA
- Department of Bioinformatics and Biochemistry, Braunschweig Integrated Centre of Systems Biology (BRICS), Technische Universität Braunschweig, Braunschweig, 38106, Germany
| | - Gurpreet K Arora
- Cell and Molecular Biology of Cancer Program, Sanford Burnham Prebys, La Jolla, CA, 92037, USA
| | - Marc Ruiz-Martinez
- Department of Pathology and Laboratory Medicine and Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Miguel Reina-Campos
- School of Biological Sciences, Department of Molecular Biology, University of California San Diego, San Diego, CA, USA
| | - Hiroaki Kasashima
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka city, 545-8585, Japan
| | - Masakazu Yashiro
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka city, 545-8585, Japan
| | - Kiyoshi Maeda
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka city, 545-8585, Japan
| | - Ana Albaladejo-Gonzalez
- Department of Histology and Pathology, Faculty of Life Sciences, Universidad Católica de Murcia (UCAM), 30107, Murcia, Spain
- Department of Pathology, Santa Lucía General University Hospital (HGUSL), Calle Mezquita sn, 30202, Cartagena, Spain
| | - Daniel Torres-Moreno
- Department of Histology and Pathology, Faculty of Life Sciences, Universidad Católica de Murcia (UCAM), 30107, Murcia, Spain
- Department of Clinical Analysis, Santa Lucía General University Hospital (HGUSL), Calle Mezquita sn, 30202, Cartagena, Spain
| | - José García-Solano
- Department of Histology and Pathology, Faculty of Life Sciences, Universidad Católica de Murcia (UCAM), 30107, Murcia, Spain
- Department of Pathology, Santa Lucía General University Hospital (HGUSL), Calle Mezquita sn, 30202, Cartagena, Spain
| | - Pablo Conesa-Zamora
- Department of Histology and Pathology, Faculty of Life Sciences, Universidad Católica de Murcia (UCAM), 30107, Murcia, Spain
- Department of Clinical Analysis, Santa Lucía General University Hospital (HGUSL), Calle Mezquita sn, 30202, Cartagena, Spain
| | - Giorgio Inghirami
- Department of Pathology and Laboratory Medicine and Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Christian M Metallo
- Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA
| | - Timothy F Osborne
- Division of Endocrinology, Diabetes and Metabolism, Johns Hopkins University School of Medicine, Institute for Fundamental Biomedical Research, Johns Hopkins All Children's Hospital, St, Petersburg, FL, USA
| | - Maria T Diaz-Meco
- Department of Pathology and Laboratory Medicine and Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA.
| | - Jorge Moscat
- Department of Pathology and Laboratory Medicine and Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA.
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16
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Spaan CN, de Boer RJ, Smit WL, van der Meer JH, van Roest M, Vermeulen JL, Koelink PJ, Becker MA, Go S, Silva J, Faller WJ, van den Brink GR, Muncan V, Heijmans J. Grp78 is required for intestinal Kras-dependent glycolysis proliferation and adenomagenesis. Life Sci Alliance 2023; 6:e202301912. [PMID: 37643866 PMCID: PMC10465924 DOI: 10.26508/lsa.202301912] [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: 01/09/2023] [Revised: 08/09/2023] [Accepted: 08/11/2023] [Indexed: 08/31/2023] Open
Abstract
In development of colorectal cancer, mutations in APC are often followed by mutations in oncogene KRAS The latter changes cellular metabolism and is associated with the Warburg phenomenon. Glucose-regulated protein 78 (Grp78) is an important regulator of the protein-folding machinery, involved in processing and localization of transmembrane proteins. We hypothesize that targeting Grp78 in Apc and Kras (AK)-mutant intestines interferes with the metabolic phenotype imposed by Kras mutations. In mice with intestinal epithelial mutations in Apc, Kras G12D and heterozygosity for Grp78 (AK-Grp78 HET ) adenoma number and size is decreased compared with AK-Grp78 WT mice. Organoids from AK-Grp78 WT mice exhibited a glycolysis metabolism which was completely rescued by Grp78 heterozygosity. Expression and correct localization of glucose transporter GLUT1 was diminished in AK-Grp78 HET cells. GLUT1 inhibition restrained the increased growth observed in AK-mutant organoids, whereas AK-Grp78 HET organoids were unaffected. We identify Grp78 as a critical factor in Kras-mutated adenomagenesis. This can be attributed to a critical role for Grp78 in GLUT1 expression and localization, targeting glycolysis and the Warburg effect.
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Affiliation(s)
- Claudia N Spaan
- Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
- Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, Amsterdam, Netherlands
| | - Ruben J de Boer
- Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
- Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, Amsterdam, Netherlands
| | - Wouter L Smit
- Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
- Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, Amsterdam, Netherlands
| | - Jonathan Hm van der Meer
- Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, Amsterdam, Netherlands
| | - Manon van Roest
- Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, Amsterdam, Netherlands
| | - Jacqueline Lm Vermeulen
- Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, Amsterdam, Netherlands
| | - Pim J Koelink
- Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, Amsterdam, Netherlands
| | - Marte Aj Becker
- Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, Amsterdam, Netherlands
| | - Simei Go
- Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, Amsterdam, Netherlands
| | - Joana Silva
- Department of Oncogenomics, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - William J Faller
- Department of Oncogenomics, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Gijs R van den Brink
- Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Vanesa Muncan
- Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, Amsterdam, Netherlands
| | - Jarom Heijmans
- Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
- Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, Netherlands
- Department of Internal Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, Amsterdam, Netherlands
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17
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Moreta-Moraleda C, Queralt C, Vendrell-Ayats C, Forcales S, Martínez-Balibrea E. Chromatin factors: Ready to roll as biomarkers in metastatic colorectal cancer? Pharmacol Res 2023; 196:106924. [PMID: 37709185 DOI: 10.1016/j.phrs.2023.106924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 08/29/2023] [Accepted: 09/12/2023] [Indexed: 09/16/2023]
Abstract
Colorectal cancer (CRC) ranks as the third most prevalent cancer globally and stands as the fourth leading cause of cancer-related fatalities in 2020. Survival rates for metastatic disease have slightly improved in recent decades, with clinical trials showing median overall survival of approximately 24-30 months. This progress can be attributed to the integration of chemotherapeutic treatments alongside targeted therapies and immunotherapy. Despite these modest improvements, the primary obstacle to successful treatment for advanced CRC lies in the development of chemoresistance, whether inherent or acquired, which remains the major cause of treatment failure. Epigenetics has emerged as a hallmark of cancer, contributing to master transcription regulation and genome stability maintenance. As a result, epigenetic factors are starting to appear as potential clinical biomarkers for diagnosis, prognosis, and prediction of treatment response in CRC.In recent years, numerous studies have investigated the influence of DNA methylation, histone modifications, and chromatin remodelers on responses to chemotherapeutic treatments. While there is accumulating evidence indicating their significant involvement in various types of cancers, the exact relationship between chromatin landscapes and treatment modulation in CRC remains elusive. This review aims to provide a comprehensive summary of the most pertinent and extensively researched epigenetic-associated mechanisms described between 2015 and 2022 and their potential usefulness as predictive biomarkers in the metastatic disease.
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Affiliation(s)
- Cristina Moreta-Moraleda
- Immunology Unit, Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, University of Barcelona, c/Feixa Llarga s/n, 08917 L'Hospitalet de Llobregat, Barcelona, Spain; Group of Inflammation, Immunity and Cancer, Molecular Mechanisms and Experimental Therapy in Oncology Program (Oncobell), The Bellvitge Biomedical Research Institute ( IDIBELL), Hospital Duran i Reynals 3a Planta, Av. Gran Via de l'Hospitalet 199, 08908 L'Hospitalet de Llobregat, Spain
| | - Cristina Queralt
- ProCURE Program, Catalan Instiute of Oncology, Carretera de Can Ruti, camí de les escoles s/n, 08916 Badalona, Spain
| | - Carla Vendrell-Ayats
- ProCURE Program, Catalan Instiute of Oncology, Carretera de Can Ruti, camí de les escoles s/n, 08916 Badalona, Spain; CARE Program, Germans Trias I Pujol Research Institute (IGTP), Carretera de Can Ruti, camí de les escoles s/n, 08916 Badalona, Spain
| | - Sonia Forcales
- Serra Húnter Programme, Immunology Unit, Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, University of Barcelona, c/Feixa Llarga s/n, 08917 L'Hospitalet de Llobregat, Barcelona, Spain; Group of Inflammation, Immunity and Cancer, Molecular Mechanisms and Experimental Therapy in Oncology Program (Oncobell), The Bellvitge Biomedical Research Institute ( IDIBELL), Hospital Duran i Reynals 3a Planta, Av. Gran Via de l'Hospitalet 199, 08908 L'Hospitalet de Llobregat, Spain.
| | - Eva Martínez-Balibrea
- ProCURE Program, Catalan Instiute of Oncology, Carretera de Can Ruti, camí de les escoles s/n, 08916 Badalona, Spain; CARE Program, Germans Trias I Pujol Research Institute (IGTP), Carretera de Can Ruti, camí de les escoles s/n, 08916 Badalona, Spain.
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18
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Garbarino O, Lambroia L, Basso G, Marrella V, Franceschini B, Soldani C, Pasqualini F, Giuliano D, Costa G, Peano C, Barbarossa D, Annarita D, Salvati A, Terracciano L, Torzilli G, Donadon M, Faggioli F. Spatial resolution of cellular senescence dynamics in human colorectal liver metastasis. Aging Cell 2023:e13853. [PMID: 37157887 PMCID: PMC10352575 DOI: 10.1111/acel.13853] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 04/03/2023] [Accepted: 04/03/2023] [Indexed: 05/10/2023] Open
Abstract
Hepatic metastasis is a clinical challenge for colorectal cancer (CRC). Senescent cancer cells accumulate in CRC favoring tumor dissemination. Whether this mechanism progresses also in metastasis is unexplored. Here, we integrated spatial transcriptomics, 3D-microscopy, and multicellular transcriptomics to study the role of cellular senescence in human colorectal liver metastasis (CRLM). We discovered two distinct senescent metastatic cancer cell (SMCC) subtypes, transcriptionally located at the opposite pole of epithelial (e) to mesenchymal (m) transition. SMCCs differ in chemotherapy susceptibility, biological program, and prognostic roles. Mechanistically, epithelial (e)SMCC initiation relies on nucleolar stress, whereby c-myc dependent oncogene hyperactivation induces ribosomal RPL11 accumulation and DNA damage response. In a 2D pre-clinical model, we demonstrated that RPL11 co-localized with HDM2, a p53-specific ubiquitin ligase, leading to senescence activation in (e)SMCCs. On the contrary, mesenchymal (m)SMCCs undergo TGFβ paracrine activation of NOX4-p15 effectors. SMCCs display opposing effects also in the immune regulation of neighboring cells, establishing an immunosuppressive environment or leading to an active immune workflow. Both SMCC signatures are predictive biomarkers whose unbalanced ratio determined the clinical outcome in CRLM and CRC patients. Altogether, we provide a comprehensive new understanding of the role of SMCCs in CRLM and highlight their potential as new therapeutic targets to limit CRLM progression.
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Affiliation(s)
| | - Luca Lambroia
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Gianluca Basso
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Veronica Marrella
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
- Institute of Genetics and Biomedical Research, UoS of Milan, National Research Council, Milan, Italy
| | - Barbara Franceschini
- Department of Hepatobiliary and General Surgery, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Cristiana Soldani
- Department of Hepatobiliary and General Surgery, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Fabio Pasqualini
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
- Department of Biomedical Science, Humanitas University, Pieve Emanuele (MI), Italy
| | | | - Guido Costa
- Department of Hepatobiliary and General Surgery, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
- Department of Biomedical Science, Humanitas University, Pieve Emanuele (MI), Italy
| | - Clelia Peano
- Institute of Genetics and Biomedical Research, UoS of Milan, National Research Council, Milan, Italy
- Fondazione Human Technopole, Milan, Italy
| | | | - Destro Annarita
- Department of Pathology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Andreina Salvati
- Department of Pathology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Luigi Terracciano
- Department of Biomedical Science, Humanitas University, Pieve Emanuele (MI), Italy
- Department of Pathology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Guido Torzilli
- Department of Hepatobiliary and General Surgery, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
- Department of Biomedical Science, Humanitas University, Pieve Emanuele (MI), Italy
| | - Matteo Donadon
- Department of Hepatobiliary and General Surgery, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
- Department of Biomedical Science, Humanitas University, Pieve Emanuele (MI), Italy
| | - Francesca Faggioli
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
- Institute of Genetics and Biomedical Research, UoS of Milan, National Research Council, Milan, Italy
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19
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Neto Í, Rocha J, Gaspar MM, Reis CP. Experimental Murine Models for Colorectal Cancer Research. Cancers (Basel) 2023; 15:2570. [PMID: 37174036 PMCID: PMC10177088 DOI: 10.3390/cancers15092570] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 04/25/2023] [Accepted: 04/26/2023] [Indexed: 05/15/2023] Open
Abstract
Colorectal cancer (CRC) is the third most prevalent malignancy worldwide and in both sexes. Numerous animal models for CRC have been established to study its biology, namely carcinogen-induced models (CIMs) and genetically engineered mouse models (GEMMs). CIMs are valuable for assessing colitis-related carcinogenesis and studying chemoprevention. On the other hand, CRC GEMMs have proven to be useful for evaluating the tumor microenvironment and systemic immune responses, which have contributed to the discovery of novel therapeutic approaches. Although metastatic disease can be induced by orthotopic injection of CRC cell lines, the resulting models are not representative of the full genetic diversity of the disease due to the limited number of cell lines suitable for this purpose. On the other hand, patient-derived xenografts (PDX) are the most reliable for preclinical drug development due to their ability to retain pathological and molecular characteristics. In this review, the authors discuss the various murine CRC models with a focus on their clinical relevance, benefits, and drawbacks. From all models discussed, murine CRC models will continue to be an important tool in advancing our understanding and treatment of this disease, but additional research is required to find a model that can correctly reflect the pathophysiology of CRC.
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Affiliation(s)
- Íris Neto
- Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal; (Í.N.); (J.R.)
| | - João Rocha
- Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal; (Í.N.); (J.R.)
| | - Maria Manuela Gaspar
- Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal; (Í.N.); (J.R.)
| | - Catarina P. Reis
- Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal; (Í.N.); (J.R.)
- Instituto de Biofísica e Engenharia Biomédica (IBEB), Faculdade de Ciências, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal
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20
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Martínez-Zamudio RI, Stefa A, Nabuco Leva Ferreira Freitas JA, Vasilopoulos T, Simpson M, Doré G, Roux PF, Galan MA, Chokshi RJ, Bischof O, Herbig U. Escape from oncogene-induced senescence is controlled by POU2F2 and memorized by chromatin scars. CELL GENOMICS 2023; 3:100293. [PMID: 37082139 PMCID: PMC10112333 DOI: 10.1016/j.xgen.2023.100293] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 01/13/2023] [Accepted: 03/02/2023] [Indexed: 04/22/2023]
Abstract
Although oncogene-induced senescence (OIS) is a potent tumor-suppressor mechanism, recent studies revealed that cells could escape from OIS with features of transformed cells. However, the mechanisms that promote OIS escape remain unclear, and evidence of post-senescent cells in human cancers is missing. Here, we unravel the regulatory mechanisms underlying OIS escape using dynamic multidimensional profiling. We demonstrate a critical role for AP1 and POU2F2 transcription factors in escape from OIS and identify senescence-associated chromatin scars (SACSs) as an epigenetic memory of OIS detectable during colorectal cancer progression. POU2F2 levels are already elevated in precancerous lesions and as cells escape from OIS, and its expression and binding activity to cis-regulatory elements are associated with decreased patient survival. Our results support a model in which POU2F2 exploits a precoded enhancer landscape necessary for senescence escape and reveal POU2F2 and SACS gene signatures as valuable biomarkers with diagnostic and prognostic potential.
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Affiliation(s)
- Ricardo Iván Martínez-Zamudio
- Center for Cell Signaling, Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers University, Newark, NJ 07103, USA
- Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ 08854, USA
| | - Alketa Stefa
- Center for Cell Signaling, Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers University, Newark, NJ 07103, USA
- Graduate School of Biomedical and Health Sciences, Rutgers University, Newark, NJ 07103 USA
| | - José Américo Nabuco Leva Ferreira Freitas
- Sorbonne Université, UMR 8256, Biological Adaptation and Ageing – IBPS, 75005 Paris, France
- INSERM U1164, 75005 Paris, France
- IMRB, Mondor Institute for Biomedical Research, INSERM U955 – Université Paris Est Créteil, UPEC, Faculté de Médecine de Créteil 8, rue du Général Sarrail, 94010 Créteil, France
| | - Themistoklis Vasilopoulos
- Center for Cell Signaling, Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers University, Newark, NJ 07103, USA
- Graduate School of Biomedical and Health Sciences, Rutgers University, Newark, NJ 07103 USA
| | - Mark Simpson
- Center for Cell Signaling, Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers University, Newark, NJ 07103, USA
| | - Gregory Doré
- Institut Pasteur, Plasmodium RNA Biology Unit, 25 Rue du Docteur Roux, 75724 Cedex 15 Paris, France
| | - Pierre-François Roux
- IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut Régional du Cancer de Montpellier, Montpellier, France
| | - Mark A. Galan
- Department of Pathology and Laboratory Medicine, New Jersey Medical School, Rutgers University, Newark, NJ 07103, USA
| | - Ravi J. Chokshi
- Department of Surgery, New Jersey Medical School, Rutgers University, Newark, NJ 07103, USA
| | - Oliver Bischof
- IMRB, Mondor Institute for Biomedical Research, INSERM U955 – Université Paris Est Créteil, UPEC, Faculté de Médecine de Créteil 8, rue du Général Sarrail, 94010 Créteil, France
| | - Utz Herbig
- Center for Cell Signaling, Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers University, Newark, NJ 07103, USA
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21
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Cotarelo CL, Schad A, Schmidt M, Hönig A, Sleeman JP, Thaler S. Detection of Cellular Senescence Reveals the Existence of Senescent Tumor Cells within Invasive Breast Carcinomas and Related Metastases. Cancers (Basel) 2023; 15:cancers15061860. [PMID: 36980745 PMCID: PMC10047432 DOI: 10.3390/cancers15061860] [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: 02/22/2023] [Revised: 03/06/2023] [Accepted: 03/14/2023] [Indexed: 03/30/2023] Open
Abstract
Oncogene-induced senescence is thought to constitute a barrier to carcinogenesis by arresting cells at risk of malignant transformation. However, numerous findings suggest that senescent cells may conversely promote tumor growth and metastatic progression, for example, through the senescence-associated secretory phenotype (SASP) they produce. Here, we investigated the degree to which senescent tumor cells exist within untreated human primary breast carcinomas and whether the presence of senescent cancer cells in primary tumors is recapitulated in their matched lymph node metastases. For the detection of senescence, we used SA-β-galactosidase (SA-β-gal) staining and other senescence markers such as Ki67, p21, p53, and p16. In patients with invasive luminal A and B breast carcinomas, we found broad similarities in the appearance of cancer cells between primary tumors and their corresponding metastases. Analysis of lymph nodes from patients with other breast cancer subtypes also revealed senescent tumor cells within metastatic lesions. Collectively, our findings show that senescent tumor cells exist within primary breast carcinomas and metastatic lesions. These results suggest a potential role for senescent breast tumor cells during metastatic progression and raise the question as to whether the targeting of senescent tumor cells with anti-senescent drugs might represent a novel avenue for improved treatment of breast and other cancers.
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Affiliation(s)
- Cristina L Cotarelo
- Institute of Pathology, University Medical Center Mannheim, University of Heidelberg, 68167 Mannheim, Germany
| | - Arno Schad
- Institute of Pathology, University Medical Center, Johannes Gutenberg University, 55131 Mainz, Germany
| | - Marcus Schmidt
- Department of Gynecology and Obstetrics, University Medical Center, Johannes Gutenberg University, 55131 Mainz, Germany
| | - Arnd Hönig
- Breast Center, Women's Hospital, Marienhaus Hospital Mainz, 55131 Mainz, Germany
| | - Jonathan P Sleeman
- European Center for Angioscience, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany
- Institute of Biological and Chemical Systems-Biological Information Processing (IBCS-BIP), Karlsruhe Institute of Technology (KIT), Campus Nord, 76344 Eggenstein-Leopoldshafen, Germany
| | - Sonja Thaler
- European Center for Angioscience, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany
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22
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Paul MC, Schneeweis C, Falcomatà C, Shan C, Rossmeisl D, Koutsouli S, Klement C, Zukowska M, Widholz SA, Jesinghaus M, Heuermann KK, Engleitner T, Seidler B, Sleiman K, Steiger K, Tschurtschenthaler M, Walter B, Weidemann SA, Pietsch R, Schnieke A, Schmid RM, Robles MS, Andrieux G, Boerries M, Rad R, Schneider G, Saur D. Non-canonical functions of SNAIL drive context-specific cancer progression. Nat Commun 2023; 14:1201. [PMID: 36882420 PMCID: PMC9992512 DOI: 10.1038/s41467-023-36505-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 02/03/2023] [Indexed: 03/09/2023] Open
Abstract
SNAIL is a key transcriptional regulator in embryonic development and cancer. Its effects in physiology and disease are believed to be linked to its role as a master regulator of epithelial-to-mesenchymal transition (EMT). Here, we report EMT-independent oncogenic SNAIL functions in cancer. Using genetic models, we systematically interrogated SNAIL effects in various oncogenic backgrounds and tissue types. SNAIL-related phenotypes displayed remarkable tissue- and genetic context-dependencies, ranging from protective effects as observed in KRAS- or WNT-driven intestinal cancers, to dramatic acceleration of tumorigenesis, as shown in KRAS-induced pancreatic cancer. Unexpectedly, SNAIL-driven oncogenesis was not associated with E-cadherin downregulation or induction of an overt EMT program. Instead, we show that SNAIL induces bypass of senescence and cell cycle progression through p16INK4A-independent inactivation of the Retinoblastoma (RB)-restriction checkpoint. Collectively, our work identifies non-canonical EMT-independent functions of SNAIL and unravel its complex context-dependent role in cancer.
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Affiliation(s)
- Mariel C Paul
- Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.,Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany
| | - Christian Schneeweis
- Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.,Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany.,Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany.,Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany
| | - Chiara Falcomatà
- Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.,Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany.,Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany
| | - Chuan Shan
- Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.,Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany
| | - Daniel Rossmeisl
- Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.,Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany.,Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany
| | - Stella Koutsouli
- Institute of Medical Psychology, Faculty of Medicine, LMU Munich, Goethe Str. 31, 80336, Munich, Germany
| | - Christine Klement
- Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany.,Institute of Molecular Oncology and Functional Genomics, School of Medicine, Technische Universität München, 81675, Munich, Germany.,German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Munich, Munich, Germany
| | - Magdalena Zukowska
- Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.,Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany.,Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany
| | - Sebastian A Widholz
- Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany.,Institute of Molecular Oncology and Functional Genomics, School of Medicine, Technische Universität München, 81675, Munich, Germany.,German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Munich, Munich, Germany
| | - Moritz Jesinghaus
- Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.,Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany.,Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany.,Institute of Pathology, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany.,Institute of Pathology, University Hospital Marburg, Baldingerstraße, 35043, Marburg, Germany
| | - Konstanze K Heuermann
- Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.,Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany.,Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany
| | - Thomas Engleitner
- Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany.,Institute of Molecular Oncology and Functional Genomics, School of Medicine, Technische Universität München, 81675, Munich, Germany.,German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Munich, Munich, Germany
| | - Barbara Seidler
- Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.,Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany.,Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany
| | - Katia Sleiman
- Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.,Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany.,Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany
| | - Katja Steiger
- Institute of Pathology, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany
| | - Markus Tschurtschenthaler
- Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.,Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany.,Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany
| | - Benjamin Walter
- Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany
| | - Sören A Weidemann
- Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.,Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany.,Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany
| | - Regina Pietsch
- Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.,Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany.,Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany
| | - Angelika Schnieke
- Livestock Biotechnology, School of Life Sciences, Technische Universität München, Liesel-Beckmann Str. 1, 85354, Freising, Germany
| | - Roland M Schmid
- Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany
| | - Maria S Robles
- Institute of Medical Psychology, Faculty of Medicine, LMU Munich, Goethe Str. 31, 80336, Munich, Germany
| | - Geoffroy Andrieux
- Institute of Medical Bioinformatics and Systems Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79110, Freiburg, Germany.,German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Freiburg, 79106, Freiburg, Germany
| | - Melanie Boerries
- Institute of Medical Bioinformatics and Systems Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79110, Freiburg, Germany.,German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Freiburg, 79106, Freiburg, Germany
| | - Roland Rad
- Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany.,Institute of Molecular Oncology and Functional Genomics, School of Medicine, Technische Universität München, 81675, Munich, Germany.,German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Munich, Munich, Germany
| | - Günter Schneider
- Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.,Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany.,Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany.,University Medical Center Göttingen, Department of General, Visceral and Pediatric Surgery, 37075, Göttingen, Germany
| | - Dieter Saur
- Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. .,Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany. .,Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany. .,Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany.
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23
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Domen A, Deben C, Verswyvel J, Flieswasser T, Prenen H, Peeters M, Lardon F, Wouters A. Cellular senescence in cancer: clinical detection and prognostic implications. J Exp Clin Cancer Res 2022; 41:360. [PMID: 36575462 PMCID: PMC9793681 DOI: 10.1186/s13046-022-02555-3] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 11/30/2022] [Indexed: 12/28/2022] Open
Abstract
Cellular senescence is a state of stable cell-cycle arrest with secretory features in response to cellular stress. Historically, it has been considered as an endogenous evolutionary homeostatic mechanism to eliminate damaged cells, including damaged cells which are at risk of malignant transformation, thereby protecting against cancer. However, accumulation of senescent cells can cause long-term detrimental effects, mainly through the senescence-associated secretory phenotype, and paradoxically contribute to age-related diseases including cancer. Besides its role as tumor suppressor, cellular senescence is increasingly being recognized as an in vivo response in cancer patients to various anticancer therapies. Its role in cancer is ambiguous and even controversial, and senescence has recently been promoted as an emerging hallmark of cancer because of its hallmark-promoting capabilities. In addition, the prognostic implications of cellular senescence have been underappreciated due to the challenging detection and sparse in and ex vivo evidence of cellular senescence in cancer patients, which is only now catching up. In this review, we highlight the approaches and current challenges of in and ex vivo detection of cellular senescence in cancer patients, and we discuss the prognostic implications of cellular senescence based on in and ex vivo evidence in cancer patients.
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Affiliation(s)
- Andreas Domen
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, 2610, Wilrijk (Antwerp), Belgium.
- Department of Oncology, Antwerp University Hospital (UZA), 2650, Edegem (Antwerp), Belgium.
| | - Christophe Deben
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, 2610, Wilrijk (Antwerp), Belgium
| | - Jasper Verswyvel
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, 2610, Wilrijk (Antwerp), Belgium
| | - Tal Flieswasser
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, 2610, Wilrijk (Antwerp), Belgium
| | - Hans Prenen
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, 2610, Wilrijk (Antwerp), Belgium
- Department of Oncology, Antwerp University Hospital (UZA), 2650, Edegem (Antwerp), Belgium
| | - Marc Peeters
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, 2610, Wilrijk (Antwerp), Belgium
- Department of Oncology, Antwerp University Hospital (UZA), 2650, Edegem (Antwerp), Belgium
| | - Filip Lardon
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, 2610, Wilrijk (Antwerp), Belgium
| | - An Wouters
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, 2610, Wilrijk (Antwerp), Belgium
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24
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Active Loading of Pectin Hydrogels for Targeted Drug Delivery. Polymers (Basel) 2022; 15:polym15010092. [PMID: 36616442 PMCID: PMC9824191 DOI: 10.3390/polym15010092] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 12/09/2022] [Accepted: 12/13/2022] [Indexed: 12/28/2022] Open
Abstract
Hydrogels provide a promising method for the targeted delivery of protein drugs. Loading the protein drug into the hydrogel free volume can be challenging due to limited quantities of the drug (e.g., growth factor) and complex physicochemical properties of the hydrogel. Here, we investigated both passive and active loading of the heteropolysaccharide hydrogel pectin. Passive loading of glass phase pectin films was evaluated by contact angles and fractional thickness of the pectin films. Four pectin sources demonstrated mean contact angles of 88° with water and 122° with pleural fluid (p < 0.05). Slow kinetics and evaporative losses precluded passive loading. In contrast, active loading of the translucent pectin films was evaluated with the colorimetric tracer methylene blue. Active loading parameters were systematically varied and recorded at 500 points/s. The distribution of the tracer was evaluated by image morphometry. Active loading of the tracer into the pectin films required the optimization of probe velocity, compression force, and contact time. We conclude that active loading using pectin-specific conditions is required for the efficient embedding of low viscosity liquids into pectin hydrogels.
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25
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Li J, Wang Y, Luo Y, Liu Y, Yi Y, Li J, Pan Y, Li W, You W, Hu Q, Zhao Z, Zhang Y, Cao Y, Zhang L, Yuan J, Xiao ZXJ. USP5-Beclin 1 axis overrides p53-dependent senescence and drives Kras-induced tumorigenicity. Nat Commun 2022; 13:7799. [PMID: 36528652 PMCID: PMC9759531 DOI: 10.1038/s41467-022-35557-y] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 12/09/2022] [Indexed: 12/23/2022] Open
Abstract
Non-small cell lung cancers (NSCLC) frequently contain KRAS mutation but retain wild-type TP53. Abundant senescent cells are observed in premalignant but not in malignant tumors derived from the Kras-driven mouse model, suggesting that KRAS oncogenic signaling would have to overcome the intrinsic senescence burden for cancer progression. Here, we show that the nuclear Beclin 1-mediated inhibition of p53-dependent senescence drives Kras-mediated tumorigenesis. KRAS activates USP5 to stabilize nuclear Beclin 1, leading to MDM2-mediated p53 protein instability. KrasG12D mice lacking Beclin 1 display retarded lung tumor growth. Knockdown of USP5 or knockout of Becn1 leads to increased senescence and reduced autophagy. Mechanistically, KRAS elevates ROS to induce USP5 homodimer formation by forming the C195 disulfide bond, resulting in stabilization and activation of USP5. Together, these results demonstrate that activation of the USP5-Beclin 1 axis is pivotal in overriding intrinsic p53-dependent senescence in Kras-driven lung cancer development.
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Affiliation(s)
- Juan Li
- Center of Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu, 610065, China
| | - Yang Wang
- Center of Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu, 610065, China.
| | - Yue Luo
- Center of Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu, 610065, China
| | - Yang Liu
- Center of Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu, 610065, China
| | - Yong Yi
- Center of Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu, 610065, China
| | - Jinsong Li
- Center of Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu, 610065, China
| | - Yang Pan
- Center of Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu, 610065, China
| | - Weiyuxin Li
- Center of Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu, 610065, China
| | - Wanbang You
- Center of Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu, 610065, China
| | - Qingyong Hu
- Center of Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu, 610065, China
| | - Zhiqiang Zhao
- Center of Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu, 610065, China
| | - Yujun Zhang
- Center of Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu, 610065, China
| | - Yang Cao
- Center of Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu, 610065, China
| | - Lingqiang Zhang
- State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 100850, China
| | - Junying Yuan
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Rd, Pudong, Shanghai, 201210, China
| | - Zhi-Xiong Jim Xiao
- Center of Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu, 610065, China.
- State Key Laboratory of Biotherapy, Sichuan University, Chengdu, 610041, China.
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26
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Won Y, Choi E. Mouse models of Kras activation in gastric cancer. Exp Mol Med 2022; 54:1793-1798. [PMID: 36369466 PMCID: PMC9723172 DOI: 10.1038/s12276-022-00882-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 09/06/2022] [Accepted: 09/08/2022] [Indexed: 11/13/2022] Open
Abstract
Gastric cancer has one of the highest incidence rates and is one of the leading causes of cancer-related mortality worldwide. Sequential steps within the carcinogenic process are observed in gastric cancer as well as in pancreatic cancer and colorectal cancer. Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most well-known oncogene and can be constitutively activated by somatic mutations in the gene locus. For over 2 decades, the functions of Kras activation in gastrointestinal (GI) cancers have been studied to elucidate its oncogenic roles during the carcinogenic process. Different approaches have been utilized to generate distinct in vivo models of GI cancer, and a number of mouse models have been established using Kras-inducible systems. In this review, we summarize the genetically engineered mouse models in which Kras is activated with cell-type and/or tissue-type specificity that are utilized for studying carcinogenic processes in gastric cancer as well as pancreatic cancer and colorectal cancer. We also provide a brief description of histological phenotypes and characteristics of those mouse models and the current limitations in the gastric cancer field to be investigated further.
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Affiliation(s)
- Yoonkyung Won
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - Eunyoung Choi
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, 37232, USA.
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27
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Parmar S, Easwaran H. Genetic and epigenetic dependencies in colorectal cancer development. Gastroenterol Rep (Oxf) 2022; 10:goac035. [PMID: 35975243 PMCID: PMC9373935 DOI: 10.1093/gastro/goac035] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/24/2022] [Accepted: 05/22/2022] [Indexed: 11/12/2022] Open
Abstract
Recent studies have mapped key genetic changes in colorectal cancer (CRC) that impact important pathways contributing to the multistep models for CRC initiation and development. In parallel with genetic changes, normal and cancer tissues harbor epigenetic alterations impacting regulation of critical genes that have been shown to play profound roles in the tumor initiation. Cumulatively, these molecular changes are only loosely associated with heterogenous transcriptional programs, reflecting the heterogeneity in the various CRC molecular subtypes and the paths to CRC development. Studies from mapping molecular alterations in early CRC lesions and use of experimental models suggest that the intricate dependencies of various genetic and epigenetic hits shape the early development of CRC via different pathways and its manifestation into various CRC subtypes. We highlight the dependency of epigenetic and genetic changes in driving CRC development and discuss factors affecting epigenetic alterations over time and, by extension, risk for cancer.
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Affiliation(s)
- Sehej Parmar
- Cancer Genetics and Epigenetics, Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Hariharan Easwaran
- Cancer Genetics and Epigenetics, Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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28
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Suppression of Ribose-5-Phosphate Isomerase a Induces ROS to Activate Autophagy, Apoptosis, and Cellular Senescence in Lung Cancer. Int J Mol Sci 2022; 23:ijms23147883. [PMID: 35887232 PMCID: PMC9322731 DOI: 10.3390/ijms23147883] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 07/14/2022] [Accepted: 07/15/2022] [Indexed: 02/04/2023] Open
Abstract
Ribose-5-phosphate isomerase A (RPIA) regulates tumorigenesis in liver and colorectal cancer. However, the role of RPIA in lung cancer remains obscure. Here we report that the suppression of RPIA diminishes cellular proliferation and activates autophagy, apoptosis, and cellular senescence in lung cancer cells. First, we detected that RPIA protein was increased in the human lung cancer versus adjust normal tissue via tissue array. Next, the knockdown of RPIA in lung cancer cells displayed autophagic vacuoles, enhanced acridine orange staining, GFP-LC3 punctae, accumulated autophagosomes, and showed elevated levels of LC3-II and reduced levels of p62, together suggesting that the suppression of RPIA stimulates autophagy in lung cancer cells. In addition, decreased RPIA expression induced apoptosis by increasing levels of Bax, cleaved PARP and caspase-3 and apoptotic cells. Moreover, RPIA knockdown triggered cellular senescence and increased p53 and p21 levels in lung cancer cells. Importantly, RPIA knockdown elevated reactive oxygen species (ROS) levels. Treatment of ROS scavenger N-acetyl-L-cysteine (NAC) reverts the activation of autophagy, apoptosis and cellular senescence by RPIA knockdown in lung cancer cells. In conclusion, RPIA knockdown induces ROS levels to activate autophagy, apoptosis, and cellular senescence in lung cancer cells. Our study sheds new light on RPIA suppression in lung cancer therapy.
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29
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Groll T, Silva M, Sarker RSJ, Tschurtschenthaler M, Schnalzger T, Mogler C, Denk D, Schölch S, Schraml BU, Ruland J, Rad R, Saur D, Weichert W, Jesinghaus M, Matiasek K, Steiger K. Comparative Study of the Role of Interepithelial Mucosal Mast Cells in the Context of Intestinal Adenoma-Carcinoma Progression. Cancers (Basel) 2022; 14:cancers14092248. [PMID: 35565377 PMCID: PMC9105816 DOI: 10.3390/cancers14092248] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 04/24/2022] [Accepted: 04/27/2022] [Indexed: 02/01/2023] Open
Abstract
Mast cells (MCs) are crucial players in the relationship between the tumor microenvironment (TME) and cancer cells and have been shown to influence angiogenesis and progression of human colorectal cancer (CRC). However, the role of MCs in the TME is controversially discussed as either pro- or anti-tumorigenic. Genetically engineered mouse models (GEMMs) are the most frequently used in vivo models for human CRC research. In the murine intestine there are at least three different MC subtypes: interepithelial mucosal mast cells (ieMMCs), lamina proprial mucosal mast cells (lpMMCs) and connective tissue mast cells (CTMCs). Interepithelial mucosal mast cells (ieMMCs) in (pre-)neoplastic intestinal formalin-fixed paraffin-embedded (FFPE) specimens of mouse models (total lesions n = 274) and human patients (n = 104) were immunohistochemically identified and semiquantitatively scored. Scores were analyzed along the adenoma-carcinoma sequence in humans and 12 GEMMs of small and large intestinal cancer. The presence of ieMMCs was a common finding in intestinal adenomas and carcinomas in mice and humans. The number of ieMMCs decreased in the course of colonic adenoma-carcinoma sequence in both species (p < 0.001). However, this dynamic cellular state was not observed for small intestinal murine tumors. Furthermore, ieMMC scores were higher in GEMMs with altered Wnt signaling (active β-catenin) than in GEMMs with altered MAPK signaling and wildtypes (WT). In conclusion, we hypothesize that, besides stromal MCs (lpMMCs/CTMCs), particularly the ieMMC subset is important for onset and progression of intestinal neoplasia and may interact with the adjacent neoplastic epithelial cells in dependence on the molecular environment. Moreover, our study indicates the need for adequate GEMMs for the investigation of the intestinal immunologic TME.
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Affiliation(s)
- Tanja Groll
- Institute of Pathology, School of Medicine, Technical University of Munich, 81675 Munich, Germany; (T.G.); (M.S.); (R.S.J.S.); (C.M.); (D.D.); (W.W.); (M.J.)
- Comparative Experimental Pathology (CEP), School of Medicine, Technical University of Munich, 81675 Munich, Germany
- Center for Clinical Veterinary Medicine, Institute of Veterinary Pathology, Ludwig-Maximilians-Universitaet (LMU), 80539 Munich, Germany;
| | - Miguel Silva
- Institute of Pathology, School of Medicine, Technical University of Munich, 81675 Munich, Germany; (T.G.); (M.S.); (R.S.J.S.); (C.M.); (D.D.); (W.W.); (M.J.)
| | - Rim Sabrina Jahan Sarker
- Institute of Pathology, School of Medicine, Technical University of Munich, 81675 Munich, Germany; (T.G.); (M.S.); (R.S.J.S.); (C.M.); (D.D.); (W.W.); (M.J.)
- Comparative Experimental Pathology (CEP), School of Medicine, Technical University of Munich, 81675 Munich, Germany
| | - Markus Tschurtschenthaler
- Department of Medicine II, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany; (M.T.); (R.R.); (D.S.)
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Partner Site Munich, 81675 Munich, Germany;
- TranslaTUM, Center for Translational Cancer Research, Technical University of Munich, 81675 Munich, Germany;
- Institute of Translational Cancer Research and Experimental Cancer Therapy, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany
| | - Theresa Schnalzger
- TranslaTUM, Center for Translational Cancer Research, Technical University of Munich, 81675 Munich, Germany;
- Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, 81675 Munich, Germany
| | - Carolin Mogler
- Institute of Pathology, School of Medicine, Technical University of Munich, 81675 Munich, Germany; (T.G.); (M.S.); (R.S.J.S.); (C.M.); (D.D.); (W.W.); (M.J.)
- Comparative Experimental Pathology (CEP), School of Medicine, Technical University of Munich, 81675 Munich, Germany
| | - Daniela Denk
- Institute of Pathology, School of Medicine, Technical University of Munich, 81675 Munich, Germany; (T.G.); (M.S.); (R.S.J.S.); (C.M.); (D.D.); (W.W.); (M.J.)
- Comparative Experimental Pathology (CEP), School of Medicine, Technical University of Munich, 81675 Munich, Germany
- Center for Clinical Veterinary Medicine, Institute of Veterinary Pathology, Ludwig-Maximilians-Universitaet (LMU), 80539 Munich, Germany;
| | - Sebastian Schölch
- JCCU Translational Surgical Oncology (A430), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany;
- DKFZ-Hector Cancer Institute at University Medical Center Mannheim, 68167 Mannheim, Germany
- Department of Surgery, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
| | - Barbara U. Schraml
- Walter Brendel Centre of Experimental Medicine, University Hospital, LMU Munich, 82152 Planegg-Martinsried, Germany;
- Biomedical Center (BMC), Institute for Cardiovascular Physiology and Pathophysiology, Faculty of Medicine, LMU Munich, 82152 Planegg-Martinsried, Germany
| | - Jürgen Ruland
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Partner Site Munich, 81675 Munich, Germany;
- TranslaTUM, Center for Translational Cancer Research, Technical University of Munich, 81675 Munich, Germany;
- Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, 81675 Munich, Germany
| | - Roland Rad
- Department of Medicine II, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany; (M.T.); (R.R.); (D.S.)
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Partner Site Munich, 81675 Munich, Germany;
- TranslaTUM, Center for Translational Cancer Research, Technical University of Munich, 81675 Munich, Germany;
- Institute of Molecular Oncology and Functional Genomics, School of Medicine, Technical University of Munich, 81675 Munich, Germany
| | - Dieter Saur
- Department of Medicine II, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany; (M.T.); (R.R.); (D.S.)
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Partner Site Munich, 81675 Munich, Germany;
- TranslaTUM, Center for Translational Cancer Research, Technical University of Munich, 81675 Munich, Germany;
- Institute of Translational Cancer Research and Experimental Cancer Therapy, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany
| | - Wilko Weichert
- Institute of Pathology, School of Medicine, Technical University of Munich, 81675 Munich, Germany; (T.G.); (M.S.); (R.S.J.S.); (C.M.); (D.D.); (W.W.); (M.J.)
- Comparative Experimental Pathology (CEP), School of Medicine, Technical University of Munich, 81675 Munich, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Partner Site Munich, 81675 Munich, Germany;
| | - Moritz Jesinghaus
- Institute of Pathology, School of Medicine, Technical University of Munich, 81675 Munich, Germany; (T.G.); (M.S.); (R.S.J.S.); (C.M.); (D.D.); (W.W.); (M.J.)
- Institute of Pathology, University Hospital Marburg, 35043 Marburg, Germany
| | - Kaspar Matiasek
- Center for Clinical Veterinary Medicine, Institute of Veterinary Pathology, Ludwig-Maximilians-Universitaet (LMU), 80539 Munich, Germany;
| | - Katja Steiger
- Institute of Pathology, School of Medicine, Technical University of Munich, 81675 Munich, Germany; (T.G.); (M.S.); (R.S.J.S.); (C.M.); (D.D.); (W.W.); (M.J.)
- Comparative Experimental Pathology (CEP), School of Medicine, Technical University of Munich, 81675 Munich, Germany
- Correspondence: ; Tel.: +49-89-4140-6075; Fax: +49-89-4140-4865
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Feunteun J, Ostyn P, Delaloge S. TUMOR CELL MALIGNANCY: A COMPLEX TRAIT BUILT THROUGH RECIPROCAL INTERACTIONS BETWEEN TUMORS AND TISSUE-BODY SYSTEM. iScience 2022; 25:104217. [PMID: 35494254 PMCID: PMC9044163 DOI: 10.1016/j.isci.2022.104217] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Since the discovery of oncogenes and tumor suppressor genes in the late past century, cancer research has been overwhelmingly focused on the genetics and biology of tumor cells and hence has addressed mostly cell-autonomous processes with emphasis on traditional driver/passenger genetic models. Nevertheless, over that same period, multiple seminal observations have accumulated highlighting the role of non-cell autonomous effectors in tumor growth and metastasis. However, given that cell autonomous and non-autonomous events are observed together at the time of diagnosis, it is in fact impossible to know whether the malignant transformation is initiated by cell autonomous oncogenic events or by non-cell autonomous conditions generated by alterations of the tissue-body ecosystem. This review aims at addressing this issue by taking the option of defining malignancy as a complex genetic trait incorporating genetically determined reciprocal interactions between tumor cells and tissue-body ecosystem.
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Affiliation(s)
- Jean Feunteun
- INSERM U981, Gustave Roussy, Université Paris-Saclay, Villejuif, France
- UMR 9019, Gustave Roussy, Université Paris-Saclay, Villejuif, France
- Corresponding author
| | - Pauline Ostyn
- UMR 9019, Gustave Roussy, Université Paris-Saclay, Villejuif, France
| | - Suzette Delaloge
- Breast Cancer Group, Gustave Roussy, Université Paris-Saclay, Villejuif, France
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Welz L, Kakavand N, Hang X, Laue G, Ito G, Silva MG, Plattner C, Mishra N, Tengen F, Ogris C, Jesinghaus M, Wottawa F, Arnold P, Kaikkonen L, Stengel S, Tran F, Das S, Kaser A, Trajanoski Z, Blumberg R, Roecken C, Saur D, Tschurtschenthaler M, Schreiber S, Rosenstiel P, Aden K. Epithelial X-Box Binding Protein 1 Coordinates Tumor Protein p53-Driven DNA Damage Responses and Suppression of Intestinal Carcinogenesis. Gastroenterology 2022; 162:223-237.e11. [PMID: 34599932 PMCID: PMC8678303 DOI: 10.1053/j.gastro.2021.09.057] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 09/21/2021] [Accepted: 09/23/2021] [Indexed: 01/03/2023]
Abstract
BACKGROUND & AIMS Throughout life, the intestinal epithelium undergoes constant self-renewal from intestinal stem cells. Together with genotoxic stressors and failing DNA repair, this self-renewal causes susceptibility toward malignant transformation. X-box binding protein 1 (XBP1) is a stress sensor involved in the unfolded protein response (UPR). We hypothesized that XBP1 acts as a signaling hub to regulate epithelial DNA damage responses. METHODS Data from The Cancer Genome Atlas were analyzed for association of XBP1 with colorectal cancer (CRC) survival and molecular interactions between XBP1 and p53 pathway activity. The role of XBP1 in orchestrating p53-driven DNA damage response was tested in vitro in mouse models of chronic intestinal epithelial cell (IEC) DNA damage (Xbp1/H2bfl/fl, Xbp1ΔIEC, H2bΔIEC, H2b/Xbp1ΔIEC) and via orthotopic tumor organoid transplantation. Transcriptome analysis of intestinal organoids was performed to identify molecular targets of Xbp1-mediated DNA damage response. RESULTS In The Cancer Genome Atlas data set of CRC, low XBP1 expression was significantly associated with poor overall survival and reduced p53 pathway activity. In vivo, H2b/Xbp1ΔIEC mice developed spontaneous intestinal carcinomas. Orthotopic tumor organoid transplantation revealed a metastatic potential of H2b/Xbp1ΔIEC-derived tumors. RNA sequencing of intestinal organoids (H2b/Xbp1fl/fl, H2bΔIEC, H2b/Xbp1ΔIEC, and H2b/p53ΔIEC) identified a transcriptional program downstream of p53, in which XBP1 directs DNA-damage-inducible transcript 4-like (Ddit4l) expression. DDIT4L inhibits mechanistic target of rapamycin-mediated phosphorylation of 4E-binding protein 1. Pharmacologic mechanistic target of rapamycin inhibition suppressed epithelial hyperproliferation via 4E-binding protein 1. CONCLUSIONS Our data suggest a crucial role for XBP1 in coordinating epithelial DNA damage responses and stem cell function via a p53-DDIT4L-dependent feedback mechanism.
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Affiliation(s)
- Lina Welz
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany; Department of Internal Medicine I, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Nassim Kakavand
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Xiang Hang
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Georg Laue
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Go Ito
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany; Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Miguel Gomes Silva
- Center for Translational Cancer Research (TranslaTUM), Technische Universität München, Munich, Germany
| | - Christina Plattner
- Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria
| | - Neha Mishra
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Felicitas Tengen
- Institute of Computational Biology, Helmholtz Zentrum München, Munich, Germany
| | - Christoph Ogris
- Institute of Computational Biology, Helmholtz Zentrum München, Munich, Germany
| | - Moritz Jesinghaus
- Institute of Pathology, University Hospital Marburg, Marburg, Germany
| | - Felix Wottawa
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Philipp Arnold
- Institute of Functional and Clinical Anatomy, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Leena Kaikkonen
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts
| | - Stefanie Stengel
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Florian Tran
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany; Department of Internal Medicine I, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Saumya Das
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts
| | - Arthur Kaser
- Division of Gastroenterology and Hepatology, Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom
| | - Zlatko Trajanoski
- Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria
| | - Richard Blumberg
- Gastroenterology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Christoph Roecken
- Department of Pathology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Dieter Saur
- Center for Translational Cancer Research (TranslaTUM), Technische Universität München, Munich, Germany
| | - Markus Tschurtschenthaler
- Center for Translational Cancer Research (TranslaTUM), Technische Universität München, Munich, Germany
| | - Stefan Schreiber
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany; Department of Internal Medicine I, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Philip Rosenstiel
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
| | - Konrad Aden
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany; Department of Internal Medicine I, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
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Combined analysis of KARS mutation and p16INK4a and p14ARF methylation status in locally advanced rectal carcinoma treated with preoperative chemoradiotherapy. ARCH BIOL SCI 2022. [DOI: 10.2298/abs220222011k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Current management of locally advanced rectal carcinoma (LARC) involves
preoperative chemoradiotherapy (preCRT) before surgery. Despite improved
local control rate, the response to preCRT of individual patients is
variable and may reflect heterogeneous biological properties among tumors of
the same clinical stage. Identifying novel molecular parameters with
predictive and/or prognostic value is of great clinical importance for a
personalized therapeutic approach. In this study, KRAS mutation status was
analyzed by direct sequencing, while methylation-specific polymerase chain
reaction (MSP) was used to examine p16INK4a and p14ARF gene methylation
status in pretreatment tumor biopsies of 60 patients with LARC. The examined
molecular changes of KRAS, p16INK4a and p14ARF genes were mutually
independent (p16INK4a/KRAS, P=0.272; p14ARF/KRAS, P=0.923; p16INK4a/p14ARF,
P=0.715). However, the simultaneous presence of p14ARF methylation and KRAS
mutation was associated with a more frequent appearance of local recurrences
and distant metastasis (P=0.027). Moreover, patients with the simultaneous
presence of p16INK4a and p14ARF methylation and KRAS mutation had
significantly shorter overall survival (P=0.011). The obtained results
strongly suggest that combined analyses of examined genetic and epigenetic
molecular alterations could contribute to the identification of LARC patient
subgroups with more aggressive tumor behavior and worse disease outcome.
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33
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Georgakopoulou E, Evangelou K, Gorgoulis VG. Premalignant lesions and cellular senescence. CELLULAR SENESCENCE IN DISEASE 2022:29-60. [DOI: 10.1016/b978-0-12-822514-1.00001-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Kane AM, Liu C, Akhter DT, McKeone DM, Bell CA, Thurecht KJ, Leggett BA, Whitehall VLJ. Curcumin Chemoprevention Reduces the Incidence of Braf Mutant Colorectal Cancer in a Preclinical Study. Dig Dis Sci 2021; 66:4326-4332. [PMID: 33387125 DOI: 10.1007/s10620-020-06752-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 11/26/2020] [Indexed: 12/17/2022]
Abstract
BACKGROUND Colorectal cancer is a leading cause of cancer-related death worldwide and approximately 20% of cases can be attributed to a mutation in the BRAF oncogene. Curcumin is a promising chemopreventive agent with various anti-cancer benefits. Although curcumin has been reported to have poor bioavailability, this limitation has been overcome by the formulation of nano-carriers. In this preclinical study, we investigated the ability of an improved formulation of curcumin to reduce the incidence of Braf mutant carcinoma. AIM To investigate curcumin as a chemopreventive for Braf mutant colorectal cancer in a preclinical study utilizing a murine model of serrated neoplasia. METHODS An intestine-specific Braf mutant murine model (BrafV637E/+/Villin-CreERT2/+) was administered curcumin micelles (240 mg/kg, n = 69) in normal drinking water. Mice in the control group consumed normal drinking water (n = 83). Mice were euthanized at 14 months and the incidence of murine serrated lesions and carcinoma in each cohort were determined by histologic examination. RESULTS At completion of the study (14 months), it was found that curcumin did not reduce the incidence or multiplicity of murine serrated lesions but did significantly reduce the number of invasive carcinomas (RR 0.83, 95% CI 0.69-0.9985, P = 0.0360) compared to control. CONCLUSIONS We have performed the first long-term study assessing curcumin's effect on the development of serrated neoplasia. We found that curcumin significantly reduces the risk of developing Braf mutant colorectal cancer. Our data supports further investigation of curcumin as a chemopreventive to reduce the risk of colorectal cancer arising via the serrated pathway.
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Affiliation(s)
- Alexandra M Kane
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. .,Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia. .,Conjoint Internal Medicine Laboratory, Pathology Queensland, Queensland Health, Brisbane, QLD, Australia.
| | - Cheng Liu
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.,Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia.,Envoi Specialist Pathologists, Brisbane, QLD, Australia
| | - Dewan T Akhter
- Centre for Advanced Imaging, Australian Institute for Bioengineering and Nanotechnology, ARC Centre of Excellence in Bio-Nano Science and Technology, The University of Queensland, Brisbane, QLD, Australia
| | - Diane M McKeone
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Craig A Bell
- Centre for Advanced Imaging, Australian Institute for Bioengineering and Nanotechnology, ARC Centre of Excellence in Bio-Nano Science and Technology, The University of Queensland, Brisbane, QLD, Australia
| | - Kristofer J Thurecht
- Centre for Advanced Imaging, Australian Institute for Bioengineering and Nanotechnology, ARC Centre of Excellence in Bio-Nano Science and Technology, The University of Queensland, Brisbane, QLD, Australia.,ARC Training Centre for Innovation in Biomedical Imaging Technology, The University of Queensland, Brisbane, QLD, Australia
| | - Barbara A Leggett
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.,Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia.,Department of Gastroenterology and Hepatology, The Royal Brisbane and Women's Hospital, Queensland Health, Brisbane, QLD, Australia
| | - Vicki L J Whitehall
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.,Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia.,Conjoint Internal Medicine Laboratory, Pathology Queensland, Queensland Health, Brisbane, QLD, Australia
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Trayssac M, Clarke CJ, Stith JL, Snider JM, Newen N, Gault CR, Hannun YA, Obeid LM. Targeting sphingosine kinase 1 (SK1) enhances oncogene-induced senescence through ceramide synthase 2 (CerS2)-mediated generation of very-long-chain ceramides. Cell Death Dis 2021; 12:27. [PMID: 33414460 PMCID: PMC7790826 DOI: 10.1038/s41419-020-03281-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 11/20/2020] [Accepted: 11/24/2020] [Indexed: 02/06/2023]
Abstract
Senescence is an antiproliferative mechanism that can suppress tumor development and can be induced by oncogenes such as genes of the Ras family. Although studies have implicated bioactive sphingolipids (SL) in senescence, the specific mechanisms remain unclear. Here, using MCF10A mammary epithelial cells, we demonstrate that oncogenic K-Ras (Kirsten rat sarcoma viral oncogene homolog) is sufficient to induce cell transformation as well as cell senescence-as revealed by increases in the percentage of cells in the G1 phase of the cell cycle, p21WAF1/Cip1/CDKN1A (p21) expression, and senescence-associated β-galactosidase activity (SA-β-gal). Furthermore, oncogenic K-Ras altered SL metabolism, with an increase of long-chain (LC) C18, C20 ceramides (Cer), and very-long-chain (VLC) C22:1, C24 Cer, and an increase of sphingosine kinase 1 (SK1) expression. Since Cer and sphingosine-1-phosphate have been shown to exert opposite effects on cellular senescence, we hypothesized that targeting SK1 could enhance oncogenic K-Ras-induced senescence. Indeed, SK1 downregulation or inhibition enhanced p21 expression and SA-β-gal in cells expressing oncogenic K-Ras and impeded cell growth. Moreover, SK1 knockdown further increased LC and VLC Cer species (C18, C20, C22:1, C24, C24:1, C26:1), especially the ones increased by oncogenic K-Ras. Fumonisin B1 (FB1), an inhibitor of ceramide synthases (CerS), reduced p21 expression induced by oncogenic K-Ras both with and without SK1 knockdown. Functionally, FB1 reversed the growth defect induced by oncogenic K-Ras, confirming the importance of Cer generation in the senescent phenotype. More specifically, downregulation of CerS2 by siRNA blocked the increase of VLC Cer (C24, C24:1, and C26:1) induced by SK1 knockdown and phenocopied the effects of FB1 on p21 expression. Taken together, these data show that targeting SK1 is a potential therapeutic strategy in cancer, enhancing oncogene-induced senescence through an increase of VLC Cer downstream of CerS2.
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Affiliation(s)
- Magali Trayssac
- Department of Medicine, Stony Brook University, Stony Brook, NY, USA
- Stony Brook Cancer Center, Stony Brook, NY, USA
| | - Christopher J Clarke
- Department of Medicine, Stony Brook University, Stony Brook, NY, USA.
- Stony Brook Cancer Center, Stony Brook, NY, USA.
| | - Jeffrey L Stith
- Department of Medicine, Stony Brook University, Stony Brook, NY, USA
- Stony Brook Cancer Center, Stony Brook, NY, USA
| | - Justin M Snider
- Department of Medicine, Stony Brook University, Stony Brook, NY, USA
- Stony Brook Cancer Center, Stony Brook, NY, USA
| | - Naomi Newen
- Department of Medicine, Stony Brook University, Stony Brook, NY, USA
- Stony Brook Cancer Center, Stony Brook, NY, USA
| | | | - Yusuf A Hannun
- Department of Medicine, Stony Brook University, Stony Brook, NY, USA.
- Stony Brook Cancer Center, Stony Brook, NY, USA.
| | - Lina M Obeid
- Department of Medicine, Stony Brook University, Stony Brook, NY, USA
- Stony Brook Cancer Center, Stony Brook, NY, USA
- Northport Veterans Affairs Medical Center, Northport, NY, USA
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36
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Matozaki T, Kotani T, Murata Y, Saito Y. Roles of Src family kinase, Ras, and mTOR signaling in intestinal epithelial homeostasis and tumorigenesis. Cancer Sci 2020; 112:16-21. [PMID: 33073467 PMCID: PMC7780047 DOI: 10.1111/cas.14702] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 10/12/2020] [Accepted: 10/14/2020] [Indexed: 12/15/2022] Open
Abstract
The turnover of intestinal epithelial cells (IECs) is relatively rapid (3-5 days in mouse and human), and this short existence and other aspects of the homeostasis of IECs are tightly regulated by various signaling pathways including Wnt-β-catenin signaling. Dysregulation of IEC homeostasis likely contributes to the development of intestinal inflammation and intestinal cancer. The roles of receptor protein tyrosine kinases and their downstream signaling molecules such as Src family kinases, Ras, and mTOR in homeostatic regulation of IEC turnover have recently been evaluated. These signaling pathways have been found to promote not only the proliferation of IECs but also the differentiation of progenitor cells into secretory cell types such as goblet cells. Of note, signaling by Src family kinases, Ras, and mTOR has been shown to oppose the Wnt-β-catenin signaling pathway and thereby to limit the number of Lgr5+ intestinal stem cells or of Paneth cells. Such cross-talk of signaling pathways is important not only for proper regulation of IEC homeostasis but for the development of intestinal tumors and potentially for anticancer therapy.
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Affiliation(s)
- Takashi Matozaki
- Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Takenori Kotani
- Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yoji Murata
- Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yasuyuki Saito
- Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan
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37
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Buj R, Chen CW, Dahl ES, Leon KE, Kuskovsky R, Maglakelidze N, Navaratnarajah M, Zhang G, Doan MT, Jiang H, Zaleski M, Kutzler L, Lacko H, Lu Y, Mills GB, Gowda R, Robertson GP, Warrick JI, Herlyn M, Imamura Y, Kimball SR, DeGraff DJ, Snyder NW, Aird KM. Suppression of p16 Induces mTORC1-Mediated Nucleotide Metabolic Reprogramming. Cell Rep 2020; 28:1971-1980.e8. [PMID: 31433975 PMCID: PMC6716532 DOI: 10.1016/j.celrep.2019.07.084] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Revised: 07/01/2019] [Accepted: 07/23/2019] [Indexed: 02/07/2023] Open
Abstract
Reprogrammed metabolism and cell cycle dysregulation are two cancer hallmarks. p16 is a cell cycle inhibitor and tumor suppressor that is upregulated during oncogene-induced senescence (OIS). Loss of p16 allows for uninhibited cell cycle progression, bypass of OIS, and tumorigenesis. Whether p16 loss affects pro-tumorigenic metabolism is unclear. We report that suppression of p16 plays a central role in reprogramming metabolism by increasing nucleotide synthesis. This occurs by activation of mTORC1 signaling, which directly mediates increased translation of the mRNA encoding ribose-5-phosphate isomerase A (RPIA), a pentose phosphate pathway enzyme. p16 loss correlates with activation of the mTORC1-RPIA axis in multiple cancer types. Suppression of RPIA inhibits proliferation only in p16-low cells by inducing senescence both in vitro and in vivo. These data reveal the molecular basis whereby p16 loss modulates pro-tumorigenic metabolism through mTORC1-mediated upregulation of nucleotide synthesis and reveals a metabolic vulnerability of p16-null cancer cells. Senescence bypass through p16 loss predisposes to transformation and tumorigenesis. Buj et al. found that the loss of p16 upregulates nucleotide metabolism through increased mTORC1-mediated translation of RPIA to bypass senescence in an RB-independent manner. Thus, the mTORC1-RPIA axis is a metabolic vulnerability for p16-null cancers.
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Affiliation(s)
- Raquel Buj
- Department of Cellular & Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, USA
| | - Chi-Wei Chen
- Department of Cellular & Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, USA
| | - Erika S Dahl
- Department of Cellular & Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, USA
| | - Kelly E Leon
- Department of Cellular & Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, USA
| | - Rostislav Kuskovsky
- A.J. Drexel Autism Institute, Drexel University, Philadelphia, PA 19104, USA
| | | | - Maithili Navaratnarajah
- Department of Cellular & Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, USA
| | - Gao Zhang
- Molecular and Cellular Oncogenesis Program and Melanoma Research Institute, The Wistar Institute, Philadelphia, PA 19104, USA
| | - Mary T Doan
- A.J. Drexel Autism Institute, Drexel University, Philadelphia, PA 19104, USA
| | - Helen Jiang
- A.J. Drexel Autism Institute, Drexel University, Philadelphia, PA 19104, USA
| | - Michael Zaleski
- Department of Pathology, Penn State College of Medicine, Hershey, PA 17033, USA
| | - Lydia Kutzler
- Department of Cellular & Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, USA
| | - Holly Lacko
- Department of Cellular & Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, USA
| | - Yiling Lu
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Gordon B Mills
- Department of Cell, Developmental & Cancer Biology, Oregon Health and Sciences University, Portland, OR 97201, USA
| | - Raghavendra Gowda
- Department of Pharmacology, Penn State College of Medicine, Hershey, PA 17033, USA
| | - Gavin P Robertson
- Department of Pharmacology, Penn State College of Medicine, Hershey, PA 17033, USA
| | - Joshua I Warrick
- Department of Pathology, Penn State College of Medicine, Hershey, PA 17033, USA
| | - Meenhard Herlyn
- Molecular and Cellular Oncogenesis Program and Melanoma Research Institute, The Wistar Institute, Philadelphia, PA 19104, USA
| | - Yuka Imamura
- Department of Pharmacology, Penn State College of Medicine, Hershey, PA 17033, USA
| | - Scot R Kimball
- Department of Cellular & Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, USA
| | - David J DeGraff
- Department of Pathology, Penn State College of Medicine, Hershey, PA 17033, USA
| | - Nathaniel W Snyder
- A.J. Drexel Autism Institute, Drexel University, Philadelphia, PA 19104, USA
| | - Katherine M Aird
- Department of Cellular & Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, USA.
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Buikhuisen JY, Torang A, Medema JP. Exploring and modelling colon cancer inter-tumour heterogeneity: opportunities and challenges. Oncogenesis 2020; 9:66. [PMID: 32647253 PMCID: PMC7347540 DOI: 10.1038/s41389-020-00250-6] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Revised: 06/10/2020] [Accepted: 06/23/2020] [Indexed: 02/06/2023] Open
Abstract
Colon cancer inter-tumour heterogeneity is installed on multiple levels, ranging from (epi)genetic driver events to signalling pathway rewiring reflected by differential gene expression patterns. Although the existence of heterogeneity in colon cancer has been recognised for a longer period of time, it is sparingly incorporated as a determining factor in current clinical practice. Here we describe how unsupervised gene expression-based classification efforts, amongst which the consensus molecular subtypes (CMS), can stratify patients in biological subgroups associated with distinct disease outcome and responses to therapy. We will discuss what is needed to extend these subtyping efforts to the clinic and we will argue that preclinical models recapitulate CMS subtypes and can be of vital use to increase our understanding of treatment response and resistance and to discover novel targets for therapy.
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Affiliation(s)
- Joyce Y Buikhuisen
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.,Oncode Institute, Amsterdam, The Netherlands
| | - Arezo Torang
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.,Oncode Institute, Amsterdam, The Netherlands
| | - Jan Paul Medema
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. .,Oncode Institute, Amsterdam, The Netherlands.
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Gui H, Husson MA, Mannan R. Correlations of morphology and molecular alterations in traditional serrated adenoma. World J Gastrointest Pathophysiol 2020; 11:78-83. [PMID: 32587787 PMCID: PMC7303981 DOI: 10.4291/wjgp.v11.i4.78] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 03/27/2020] [Accepted: 05/28/2020] [Indexed: 02/06/2023] Open
Abstract
Traditional serrated adenoma was first reported by Longacre and Fenoglio-Presier in 1990. Their initial study described main features of this lesion, but the consensus diagnostic criteria were not widely adopted until recently. Traditional serrated adenoma presents with grossly protuberant configuration and pinecone-like appearance upon endoscopy. Histologically, it is characterized by ectopic crypt formation, slit-like serration, eosinophilic cytoplasm and pencillate nuclei. Although much is now known about the morphology and molecular changes, the mechanisms underlying the morphological alterations are still not fully understood. Furthermore, the origin of traditional serrated adenoma is not completely known. We review recent studies of the traditional serrated adenoma and provide an overview on current understanding of this rare entity.
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Affiliation(s)
- Hongxing Gui
- Department of Pathology and Laboratory Medicine, Pennsylvania Hospital of the University of Pennsylvania Health System, Philadelphia, PA 19107, United States
| | - Michael A Husson
- Department of Pathology and Laboratory Medicine, Pennsylvania Hospital of the University of Pennsylvania Health System, Philadelphia, PA 19107, United States
| | - Rifat Mannan
- Department of Pathology and Laboratory Medicine, Pennsylvania Hospital of the University of Pennsylvania Health System, Philadelphia, PA 19107, United States
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40
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Fennell LJ, Kane A, Liu C, McKeone D, Fernando W, Su C, Bond C, Jamieson S, Dumenil T, Patch AM, Kazakoff SH, Pearson JV, Waddell N, Leggett B, Whitehall VLJ. APC Mutation Marks an Aggressive Subtype of BRAF Mutant Colorectal Cancers. Cancers (Basel) 2020; 12:E1171. [PMID: 32384699 PMCID: PMC7281581 DOI: 10.3390/cancers12051171] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 05/01/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND WNT activation is a hallmark of colorectal cancer. BRAF mutation is present in 15% of colorectal cancers, and the role of mutations in WNT signaling regulators in this context is unclear. Here, we evaluate the mutational landscape of WNT signaling regulators in BRAF mutant cancers. METHODS we performed exome-sequencing on 24 BRAF mutant colorectal cancers and analyzed these data in combination with 175 publicly available BRAF mutant colorectal cancer exomes. We assessed the somatic mutational landscape of WNT signaling regulators, and performed hotspot and driver mutation analyses to identify potential drivers of WNT signaling. The effects of Apc and Braf mutation were modelled, in vivo, using the Apcmin/+ and BrafV637/Villin-CreERT2/+ mouse, respectively. RESULTS RNF43 was the most frequently mutated WNT signaling regulator (41%). Mutations in the beta-catenin destruction complex occurred in 48% of cancers. Hotspot analyses identified potential cancer driver genes in the WNT signaling cascade, including MEN1, GNG12 and WNT16. Truncating APC mutation was identified in 20.8% of cancers. Truncating APC mutation was associated with early age at diagnosis (p < 2 × 10-5), advanced stage (p < 0.01), and poor survival (p = 0.026). Apcmin/+/BrafV637 animals had more numerous and larger SI and colonic lesions (p < 0.0001 and p < 0.05, respectively), and a markedly reduced survival (median survival: 3.2 months, p = 8.8 × 10-21), compared to animals with Apc or Braf mutation alone. CONCLUSIONS the WNT signaling axis is frequently mutated in BRAF mutant colorectal cancers. WNT16 and MEN1 may be novel drivers of aberrant WNT signaling in colorectal cancer. Co-mutation of BRAF and APC generates an extremely aggressive neoplastic phenotype that is associated with poor patient outcome.
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Affiliation(s)
- Lochlan J. Fennell
- QIMR Berghofer Medical Research Institute, Queensland 4006, Australia; (A.K.); (C.L.); (D.M.); (W.F.); (C.S.); (C.B.); (S.J.); (T.D.); (A.-M.P.); (S.H.K.); (J.V.P.); (N.W.); (B.L.); (V.L.J.W.)
- School of Medicine, The University of Queensland, Queensland 4072, Australia
| | - Alexandra Kane
- QIMR Berghofer Medical Research Institute, Queensland 4006, Australia; (A.K.); (C.L.); (D.M.); (W.F.); (C.S.); (C.B.); (S.J.); (T.D.); (A.-M.P.); (S.H.K.); (J.V.P.); (N.W.); (B.L.); (V.L.J.W.)
- School of Medicine, The University of Queensland, Queensland 4072, Australia
- Conjoint Internal Medicine Laboratory, Chemical Pathology, Pathology Queensland, Herston 4006, Australia
| | - Cheng Liu
- QIMR Berghofer Medical Research Institute, Queensland 4006, Australia; (A.K.); (C.L.); (D.M.); (W.F.); (C.S.); (C.B.); (S.J.); (T.D.); (A.-M.P.); (S.H.K.); (J.V.P.); (N.W.); (B.L.); (V.L.J.W.)
- School of Medicine, The University of Queensland, Queensland 4072, Australia
- Envoi Specialist Pathologists, Queensland 4059, Australia
| | - Diane McKeone
- QIMR Berghofer Medical Research Institute, Queensland 4006, Australia; (A.K.); (C.L.); (D.M.); (W.F.); (C.S.); (C.B.); (S.J.); (T.D.); (A.-M.P.); (S.H.K.); (J.V.P.); (N.W.); (B.L.); (V.L.J.W.)
| | - Winnie Fernando
- QIMR Berghofer Medical Research Institute, Queensland 4006, Australia; (A.K.); (C.L.); (D.M.); (W.F.); (C.S.); (C.B.); (S.J.); (T.D.); (A.-M.P.); (S.H.K.); (J.V.P.); (N.W.); (B.L.); (V.L.J.W.)
| | - Chang Su
- QIMR Berghofer Medical Research Institute, Queensland 4006, Australia; (A.K.); (C.L.); (D.M.); (W.F.); (C.S.); (C.B.); (S.J.); (T.D.); (A.-M.P.); (S.H.K.); (J.V.P.); (N.W.); (B.L.); (V.L.J.W.)
- School of Medicine, The University of Queensland, Queensland 4072, Australia
| | - Catherine Bond
- QIMR Berghofer Medical Research Institute, Queensland 4006, Australia; (A.K.); (C.L.); (D.M.); (W.F.); (C.S.); (C.B.); (S.J.); (T.D.); (A.-M.P.); (S.H.K.); (J.V.P.); (N.W.); (B.L.); (V.L.J.W.)
| | - Saara Jamieson
- QIMR Berghofer Medical Research Institute, Queensland 4006, Australia; (A.K.); (C.L.); (D.M.); (W.F.); (C.S.); (C.B.); (S.J.); (T.D.); (A.-M.P.); (S.H.K.); (J.V.P.); (N.W.); (B.L.); (V.L.J.W.)
| | - Troy Dumenil
- QIMR Berghofer Medical Research Institute, Queensland 4006, Australia; (A.K.); (C.L.); (D.M.); (W.F.); (C.S.); (C.B.); (S.J.); (T.D.); (A.-M.P.); (S.H.K.); (J.V.P.); (N.W.); (B.L.); (V.L.J.W.)
| | - Ann-Marie Patch
- QIMR Berghofer Medical Research Institute, Queensland 4006, Australia; (A.K.); (C.L.); (D.M.); (W.F.); (C.S.); (C.B.); (S.J.); (T.D.); (A.-M.P.); (S.H.K.); (J.V.P.); (N.W.); (B.L.); (V.L.J.W.)
| | - Stephen H. Kazakoff
- QIMR Berghofer Medical Research Institute, Queensland 4006, Australia; (A.K.); (C.L.); (D.M.); (W.F.); (C.S.); (C.B.); (S.J.); (T.D.); (A.-M.P.); (S.H.K.); (J.V.P.); (N.W.); (B.L.); (V.L.J.W.)
| | - John V. Pearson
- QIMR Berghofer Medical Research Institute, Queensland 4006, Australia; (A.K.); (C.L.); (D.M.); (W.F.); (C.S.); (C.B.); (S.J.); (T.D.); (A.-M.P.); (S.H.K.); (J.V.P.); (N.W.); (B.L.); (V.L.J.W.)
| | - Nicola Waddell
- QIMR Berghofer Medical Research Institute, Queensland 4006, Australia; (A.K.); (C.L.); (D.M.); (W.F.); (C.S.); (C.B.); (S.J.); (T.D.); (A.-M.P.); (S.H.K.); (J.V.P.); (N.W.); (B.L.); (V.L.J.W.)
- School of Medicine, The University of Queensland, Queensland 4072, Australia
| | - Barbara Leggett
- QIMR Berghofer Medical Research Institute, Queensland 4006, Australia; (A.K.); (C.L.); (D.M.); (W.F.); (C.S.); (C.B.); (S.J.); (T.D.); (A.-M.P.); (S.H.K.); (J.V.P.); (N.W.); (B.L.); (V.L.J.W.)
- School of Medicine, The University of Queensland, Queensland 4072, Australia
- Department of Gastroenterology and Hepatology, The Royal Brisbane and Women’s Hospital, Queensland 4006, Australia
| | - Vicki L. J. Whitehall
- QIMR Berghofer Medical Research Institute, Queensland 4006, Australia; (A.K.); (C.L.); (D.M.); (W.F.); (C.S.); (C.B.); (S.J.); (T.D.); (A.-M.P.); (S.H.K.); (J.V.P.); (N.W.); (B.L.); (V.L.J.W.)
- School of Medicine, The University of Queensland, Queensland 4072, Australia
- Conjoint Internal Medicine Laboratory, Chemical Pathology, Pathology Queensland, Herston 4006, Australia
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Bürtin F, Mullins CS, Linnebacher M. Mouse models of colorectal cancer: Past, present and future perspectives. World J Gastroenterol 2020; 26:1394-1426. [PMID: 32308343 PMCID: PMC7152519 DOI: 10.3748/wjg.v26.i13.1394] [Citation(s) in RCA: 103] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 03/05/2020] [Accepted: 03/10/2020] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common diagnosed malignancy among both sexes in the United States as well as in the European Union. While the incidence and mortality rates in western, high developed countries are declining, reflecting the success of screening programs and improved treatment regimen, a rise of the overall global CRC burden can be observed due to lifestyle changes paralleling an increasing human development index. Despite a growing insight into the biology of CRC and many therapeutic improvements in the recent decades, preclinical in vivo models are still indispensable for the development of new treatment approaches. Since the development of carcinogen-induced rodent models for CRC more than 80 years ago, a plethora of animal models has been established to study colon cancer biology. Despite tenuous invasiveness and metastatic behavior, these models are useful for chemoprevention studies and to evaluate colitis-related carcinogenesis. Genetically engineered mouse models (GEMM) mirror the pathogenesis of sporadic as well as inherited CRC depending on the specific molecular pathways activated or inhibited. Although the vast majority of CRC GEMM lack invasiveness, metastasis and tumor heterogeneity, they still have proven useful for examination of the tumor microenvironment as well as systemic immune responses; thus, supporting development of new therapeutic avenues. Induction of metastatic disease by orthotopic injection of CRC cell lines is possible, but the so generated models lack genetic diversity and the number of suited cell lines is very limited. Patient-derived xenografts, in contrast, maintain the pathological and molecular characteristics of the individual patient's CRC after subcutaneous implantation into immunodeficient mice and are therefore most reliable for preclinical drug development - even in comparison to GEMM or cell line-based analyses. However, subcutaneous patient-derived xenograft models are less suitable for studying most aspects of the tumor microenvironment and anti-tumoral immune responses. The authors review the distinct mouse models of CRC with an emphasis on their clinical relevance and shed light on the latest developments in the field of preclinical CRC models.
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Affiliation(s)
- Florian Bürtin
- Department of General, Visceral, Vascular and Transplantation Surgery, University Medical Center Rostock, University of Rostock, Rostock 18057, Germany
| | - Christina S Mullins
- Department of Thoracic Surgery, University Medical Center Rostock, University of Rostock, Rostock 18057, Germany
| | - Michael Linnebacher
- Molecular Oncology and Immunotherapy, Department of General, Visceral, Vascular and Transplantation Surgery, University Medical Center Rostock, Rostock 18057, Germany
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Rhodes SD, He Y, Smith A, Jiang L, Lu Q, Mund J, Li X, Bessler W, Qian S, Dyer W, Sandusky GE, Horvai AE, Armstrong AE, Clapp DW. Cdkn2a (Arf) loss drives NF1-associated atypical neurofibroma and malignant transformation. Hum Mol Genet 2020; 28:2752-2762. [PMID: 31091306 DOI: 10.1093/hmg/ddz095] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 04/15/2019] [Accepted: 05/06/2019] [Indexed: 02/06/2023] Open
Abstract
Plexiform neurofibroma (PN) tumors are a hallmark manifestation of neurofibromatosis type 1 (NF1) that arise in the Schwann cell (SC) lineage. NF1 is a common heritable cancer predisposition syndrome caused by germline mutations in the NF1 tumor suppressor, which encodes a GTPase-activating protein called neurofibromin that negatively regulates Ras proteins. Whereas most PN are clinically indolent, a subset progress to atypical neurofibromatous neoplasms of uncertain biologic potential (ANNUBP) and/or to malignant peripheral nerve sheath tumors (MPNSTs). In small clinical series, loss of 9p21.3, which includes the CDKN2A locus, has been associated with the genesis of ANNUBP. Here we show that the Cdkn2a alternate reading frame (Arf) serves as a gatekeeper tumor suppressor in mice that prevents PN progression by inducing senescence-mediated growth arrest in aberrantly proliferating Nf1-/- SC. Conditional ablation of Nf1 and Arf in the neural crest-derived SC lineage allows escape from senescence, resulting in tumors that accurately phenocopy human ANNUBP and progress to MPNST with high penetrance. This animal model will serve as a platform to study the clonal development of ANNUBP and MPNST and to identify new therapies to treat existing tumors and to prevent disease progression.
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Affiliation(s)
- Steven D Rhodes
- Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, 46202, USA.,Division of Pediatric Hematology-Oncology, Indiana University School of Medicine, Indianapolis, 46202, USA
| | - Yongzheng He
- Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, 46202, USA
| | - Abbi Smith
- Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, 46202, USA
| | - Li Jiang
- Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, 46202, USA
| | - Qingbo Lu
- Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, 46202, USA
| | - Julie Mund
- Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, 46202, USA
| | - Xiaohong Li
- Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, 46202, USA
| | - Waylan Bessler
- Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, 46202, USA
| | - Shaomin Qian
- Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, 46202, USA
| | - William Dyer
- Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, 46202, USA
| | - George E Sandusky
- Department of Pathology, Indiana University School of Medicine, Indianapolis, 46202, USA
| | - Andrew E Horvai
- Department of Pathology and Laboratory Medicine, University of California, San Francisco, 94143, USA
| | - Amy E Armstrong
- Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, 46202, USA.,Division of Pediatric Hematology-Oncology, Indiana University School of Medicine, Indianapolis, 46202, USA
| | - D Wade Clapp
- Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, 46202, USA
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Seo Y, Shin TH, Ahn JS, Oh SJ, Shin YY, Yang JW, Park HY, Shin SC, Kwon HK, Kim JM, Sung ES, Park GC, Lee BJ, Kim HS. Human Tonsil-Derived Mesenchymal Stromal Cells Maintain Proliferating and ROS-Regulatory Properties via Stanniocalcin-1. Cells 2020; 9:cells9030636. [PMID: 32155780 PMCID: PMC7140534 DOI: 10.3390/cells9030636] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Revised: 02/29/2020] [Accepted: 03/04/2020] [Indexed: 02/07/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) from various sources exhibit different potential for stemness and therapeutic abilities. Recently, we reported a unique MSCs from human palatine tonsil (TMSCs) and their superior proliferation capacity compared to MSCs from other sources. However, unique characteristics of each MSC are not yet precisely elucidated. We investigated the role of stanniocalcin-1 (STC1), an anti-oxidative hormone, in the functions of TMSCs. We found that STC1 was highly expressed in TMSC compared with MSCs from bone marrow or adipose tissue. The proliferation, senescence and differentiation of TMSCs were assessed after the inhibition of STC1 expression. STC1 inhibition resulted in a significant decrease in the proliferation of TMSCs and did not affect the differentiation potential. To reveal the anti-oxidative ability of STC1 in TMSCs themselves or against other cell types, the generation of mitochondrial reactive oxygen species (ROS) in TMSC or ROS-mediated production of interleukin (IL)-1β from macrophage-like cells were detected. Interestingly, the basal level of ROS generation in TMSCs was significantly elevated after STC1 inhibition. Moreover, down-regulation of STC1 impaired the inhibitory effect of TMSCs on IL-1β production in macrophages. Taken together, these findings indicate that STC1 is highly expressed in TMSCs and plays a critical role in proliferating and ROS-regulatory abilities.
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Affiliation(s)
- Yoojin Seo
- Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Korea; (Y.S.); (J.-S.A.); (S.-J.O.); (Y.Y.S.); (J.W.Y.)
- Dental and Life Science Institute, Pusan National University, Yangsan 50612, Korea
| | - Tae-Hoon Shin
- Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Korea; (T.-H.S.); (H.Y.P.)
- Translational Stem Cell Biology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Ji-Su Ahn
- Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Korea; (Y.S.); (J.-S.A.); (S.-J.O.); (Y.Y.S.); (J.W.Y.)
- Dental and Life Science Institute, Pusan National University, Yangsan 50612, Korea
| | - Su-Jeong Oh
- Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Korea; (Y.S.); (J.-S.A.); (S.-J.O.); (Y.Y.S.); (J.W.Y.)
- Dental and Life Science Institute, Pusan National University, Yangsan 50612, Korea
| | - Ye Young Shin
- Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Korea; (Y.S.); (J.-S.A.); (S.-J.O.); (Y.Y.S.); (J.W.Y.)
- Dental and Life Science Institute, Pusan National University, Yangsan 50612, Korea
| | - Ji Won Yang
- Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Korea; (Y.S.); (J.-S.A.); (S.-J.O.); (Y.Y.S.); (J.W.Y.)
- Dental and Life Science Institute, Pusan National University, Yangsan 50612, Korea
| | - Hee Young Park
- Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Korea; (T.-H.S.); (H.Y.P.)
| | - Sung-Chan Shin
- Department of Otorhinolaryngology, College of Medicine, Pusan National University and Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Korea; (S.-C.S.); (H.-K.K.); (J.M.K.)
| | - Hyun-Keun Kwon
- Department of Otorhinolaryngology, College of Medicine, Pusan National University and Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Korea; (S.-C.S.); (H.-K.K.); (J.M.K.)
| | - Ji Min Kim
- Department of Otorhinolaryngology, College of Medicine, Pusan National University and Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Korea; (S.-C.S.); (H.-K.K.); (J.M.K.)
| | - Eui-Suk Sung
- Department of Otorhinolaryngology-Head and Neck Surgery, Biomedical Research Institute, Pusan National University School of Medicine, Yangsan Pusan National University Hospital, Yangsan 50612, Korea;
| | - Gi Cheol Park
- Department of Otolaryngology – Head and Neck Surgery, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon 51353, Korea;
| | - Byung-Joo Lee
- Department of Otorhinolaryngology, College of Medicine, Pusan National University and Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Korea; (S.-C.S.); (H.-K.K.); (J.M.K.)
- Correspondence: (B.-J.L.); (H.-S.K.); Tel.: +82-51-240-7675 (B.-J.L.); +82-51-510-8231 (H.-S.K.)
| | - Hyung-Sik Kim
- Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Korea; (Y.S.); (J.-S.A.); (S.-J.O.); (Y.Y.S.); (J.W.Y.)
- Dental and Life Science Institute, Pusan National University, Yangsan 50612, Korea
- Correspondence: (B.-J.L.); (H.-S.K.); Tel.: +82-51-240-7675 (B.-J.L.); +82-51-510-8231 (H.-S.K.)
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Liu T, Guo Z, Song X, Liu L, Dong W, Wang S, Xu M, Yang C, Wang B, Cao H. High-fat diet-induced dysbiosis mediates MCP-1/CCR2 axis-dependent M2 macrophage polarization and promotes intestinal adenoma-adenocarcinoma sequence. J Cell Mol Med 2020; 24:2648-2662. [PMID: 31957197 PMCID: PMC7028862 DOI: 10.1111/jcmm.14984] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 12/05/2019] [Accepted: 12/16/2019] [Indexed: 12/17/2022] Open
Abstract
High‐fat diet (HFD) is a well‐known risk factor for gut microbiota dysbiosis and colorectal cancer (CRC). However, evidence relating HFD, gut microbiota and carcinogenesis is limited. Our study aimed to demonstrate that HFD‐induced gut dysbiosis promoted intestinal adenoma‐adenocarcinoma sequence. In clinical study, we found that HFD increased the incidence of advanced colorectal neoplasia (AN). The expression of monocyte chemoattractant protein 1 (MCP‐1), CC chemokine receptor 2 (CCR2) and CD163 in CRC patients with HFD was significantly higher than that in CRC patients with normal diet. When it comes to the Apcmin/+ mice, HFD consumption could induce gut dysbiosis and promote intestinal carcinogenesis, accompanying with activation of MCP‐1/CCR2 axis that recruited and polarized M2 tumour‐associated macrophages. Interestingly, transfer of faecal microbiota from HFD‐fed mice to another batch of Apcmin/+ mice in the absence of HFD could also enhance carcinogenesis without significant body weight gain and induced MCP‐1/CCR2 axis activation. HFD‐induced dysbiosis could also be transmitted. Meanwhile, antibiotics cocktail treatment was sufficient to inhibit HFD‐induced carcinogenesis, indicating the vital role of dysbiosis in cancer development. Conclusively, these data indicated that HFD‐induced dysbiosis accelerated intestinal adenoma‐adenocarcinoma sequence through activation of MCP‐1/CCR2 axis, which would provide new insight into better understanding of the mechanisms and prevention for HFD‐related CRC.
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Affiliation(s)
- Tianyu Liu
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Disease, Tianjin, China
| | - Zixuan Guo
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Disease, Tianjin, China
| | - Xueli Song
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Disease, Tianjin, China
| | - Li Liu
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Disease, Tianjin, China
| | - Wenxiao Dong
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Disease, Tianjin, China
| | - Sinan Wang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Disease, Tianjin, China
| | - Mengque Xu
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Disease, Tianjin, China.,Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Cheng Yang
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China.,Tianjin International Joint Academy of Biomedicine, Tianjin, China
| | - Bangmao Wang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Disease, Tianjin, China
| | - Hailong Cao
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Disease, Tianjin, China.,Tianjin International Joint Academy of Biomedicine, Tianjin, China
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Matoba H, Takamoto M, Fujii C, Kawakubo M, Kasuga E, Matsumura T, Natori T, Misawa K, Taniguchi S, Nakayama J. Cecal Tumorigenesis in Aryl Hydrocarbon Receptor-Deficient Mice Depends on Cecum-Specific Mitogen-Activated Protein Kinase Pathway Activation and Inflammation. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 190:453-468. [PMID: 31734232 DOI: 10.1016/j.ajpath.2019.10.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Revised: 10/01/2019] [Accepted: 10/08/2019] [Indexed: 02/06/2023]
Abstract
The aryl hydrocarbon receptor (AhR) is a transcription factor known as a dioxin receptor. Recently, Ahr-/- mice were revealed to develop cecal tumors with inflammation and Wnt/β-catenin pathway activation. However, whether β-catenin degradation is AhR dependent remains unclear. To determine whether other signaling pathways function in Ahr-/- cecal tumorigenesis, we investigated histologic characteristics of the tumors and cytokine/chemokine production in tumors and Ahr-/- peritoneal macrophages. AhR expression was also assessed in human colorectal carcinomas. Of the 28 Ahr-/- mice, 10 developed cecal lesions by 50 weeks of age, an incidence significantly lower than previously reported. Cecal lesions of Ahr-/- mice developed from serrated hyperplasia to adenoma/dysplasia-like neoplasia with enhanced proliferation. Macrophage and neutrophil infiltration into the lesions was also observed early in serrated hyperplasia, although adjacent mucosa was devoid of inflammation. Il1b, Il6, Ccl2, and Cxcl5 were up-regulated at lesion sites, whereas only IL-6 production increased in Ahr-/- peritoneal macrophages after lipopolysaccharide + ATP stimulation. Neither Myc (alias c-myc) up-regulation nor β-catenin nuclear translocation was observed, unlike previously reported. Interestingly, enhanced phosphorylation of extracellular signal-regulated kinase, Src, and epidermal growth factor receptor and Amphiregulin up-regulation at Ahr-/- lesion sites were detected. In human serrated lesions, however, AhR expression in epithelial cells was up-regulated despite morphologic similarity to Ahr-/- cecal lesions. Our results suggest novel mechanisms underlying Ahr-/- cecal tumorigenesis, depending primarily on cecum-specific mitogen-activated protein kinase pathway activation and inflammation.
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Affiliation(s)
- Hisanori Matoba
- Department of Molecular Pathology, Shinshu University School of Medicine, Matsumoto, Japan; Department of Pathology, Ina Central Hospital, Ina, Japan
| | - Masaya Takamoto
- Department of Infection and Host Defense and Pathobiology, Shinshu University School of Medicine, Matsumoto, Japan.
| | - Chifumi Fujii
- Department of Molecular Pathology, Shinshu University School of Medicine, Matsumoto, Japan; Department of Biotechnology, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto, Japan.
| | - Masatomo Kawakubo
- Department of Molecular Pathology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Eriko Kasuga
- Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan
| | | | - Tatsuya Natori
- Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan
| | - Ken Misawa
- Department of Pathology, Ina Central Hospital, Ina, Japan
| | - Shun'ichiro Taniguchi
- Comprehensive Cancer Therapy, Shinshu University School of Medicine, Matsumoto, Japan
| | - Jun Nakayama
- Department of Molecular Pathology, Shinshu University School of Medicine, Matsumoto, Japan
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Nakanishi Y, Diaz-Meco MT, Moscat J. Serrated Colorectal Cancer: The Road Less Travelled? Trends Cancer 2019; 5:742-754. [PMID: 31735291 DOI: 10.1016/j.trecan.2019.09.004] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 09/09/2019] [Accepted: 09/10/2019] [Indexed: 02/06/2023]
Abstract
Studies of colorectal cancer (CRC) originating through the conventional adenoma-carcinoma sequence have provided insight into the molecular mechanisms controlling its initiation and progression. Less is known about the alternative 'serrated' pathway, which has been associated with BRAF mutation and microsatellite instability. Recent transcriptomics approaches to classify human CRC revealed that mesenchymal and/or desmoplastic features combined with an immunosuppressive microenvironment are key determinants of CRC with the poorest prognosis. Importantly, these aggressive CRCs harbor the characteristics of serrated tumors, suggesting that initiation through this alternative pathway determines how aggressive the CRC becomes. Here, we review recent evidence on how serrated carcinogenesis contributes to the subtype of CRC with the poorest prognosis.
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Affiliation(s)
- Yuki Nakanishi
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan
| | - Maria T Diaz-Meco
- Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
| | - Jorge Moscat
- Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
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Jackstadt R, van Hooff SR, Leach JD, Cortes-Lavaud X, Lohuis JO, Ridgway RA, Wouters VM, Roper J, Kendall TJ, Roxburgh CS, Horgan PG, Nixon C, Nourse C, Gunzer M, Clark W, Hedley A, Yilmaz OH, Rashid M, Bailey P, Biankin AV, Campbell AD, Adams DJ, Barry ST, Steele CW, Medema JP, Sansom OJ. Epithelial NOTCH Signaling Rewires the Tumor Microenvironment of Colorectal Cancer to Drive Poor-Prognosis Subtypes and Metastasis. Cancer Cell 2019; 36:319-336.e7. [PMID: 31526760 PMCID: PMC6853173 DOI: 10.1016/j.ccell.2019.08.003] [Citation(s) in RCA: 304] [Impact Index Per Article: 50.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 05/31/2019] [Accepted: 08/06/2019] [Indexed: 12/14/2022]
Abstract
The metastatic process of colorectal cancer (CRC) is not fully understood and effective therapies are lacking. We show that activation of NOTCH1 signaling in the murine intestinal epithelium leads to highly penetrant metastasis (100% metastasis; with >80% liver metastases) in KrasG12D-driven serrated cancer. Transcriptional profiling reveals that epithelial NOTCH1 signaling creates a tumor microenvironment (TME) reminiscent of poorly prognostic human CRC subtypes (CMS4 and CRIS-B), and drives metastasis through transforming growth factor (TGF) β-dependent neutrophil recruitment. Importantly, inhibition of this recruitment with clinically relevant therapeutic agents blocks metastasis. We propose that NOTCH1 signaling is key to CRC progression and should be exploited clinically.
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Affiliation(s)
| | - Sander R van Hooff
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands
| | - Joshua D Leach
- Cancer Research UK Beatson Institute, Glasgow, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK
| | | | | | | | - Valérie M Wouters
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands
| | - Jatin Roper
- Department of Medicine, Division of Gastroenterology, Duke University, Durham, NC, USA
| | - Timothy J Kendall
- Division of Pathology/Centre for Inflammation Research, University of Edinburgh, UK
| | - Campbell S Roxburgh
- Academic Unit of Surgery, School of Medicine, University of Glasgow, Glasgow, UK
| | - Paul G Horgan
- Academic Unit of Surgery, School of Medicine, University of Glasgow, Glasgow, UK
| | - Colin Nixon
- Cancer Research UK Beatson Institute, Glasgow, UK
| | - Craig Nourse
- Cancer Research UK Beatson Institute, Glasgow, UK
| | - Matthias Gunzer
- Institute for Experimental Immunology and Imaging, University Hospital, University Duisburg-Essen, Essen, Germany
| | | | - Ann Hedley
- Cancer Research UK Beatson Institute, Glasgow, UK
| | - Omer H Yilmaz
- Division of Gastroenterology, Tufts Medical Center, Boston, MA, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
| | - Mamunur Rashid
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK
| | - Peter Bailey
- Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK
| | - Andrew V Biankin
- Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK
| | | | - David J Adams
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK
| | - Simon T Barry
- Bioscience, Oncology R&D, AstraZeneca, Cambridge, UK
| | - Colin W Steele
- Cancer Research UK Beatson Institute, Glasgow, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK
| | - Jan Paul Medema
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands
| | - Owen J Sansom
- Cancer Research UK Beatson Institute, Glasgow, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK.
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48
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Reina-Campos M, Diaz-Meco MT, Moscat J. The Dual Roles of the Atypical Protein Kinase Cs in Cancer. Cancer Cell 2019; 36:218-235. [PMID: 31474570 PMCID: PMC6751000 DOI: 10.1016/j.ccell.2019.07.010] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Revised: 06/24/2019] [Accepted: 07/30/2019] [Indexed: 02/08/2023]
Abstract
Atypical protein kinase C (aPKC) isozymes, PKCλ/ι and PKCζ, are now considered fundamental regulators of tumorigenesis. However, the specific separation of functions that determine their different roles in cancer is still being unraveled. Both aPKCs have pleiotropic context-dependent functions that can translate into tumor-promoter or -suppressive functions. Here, we review early and more recent literature to discuss how the different tumor types, and their microenvironments, might account for the selective signaling of each aPKC isotype. This is of clinical relevance because a better understanding of the roles of these kinases is essential for the design of new anti-cancer treatments.
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Affiliation(s)
- Miguel Reina-Campos
- Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA
| | - Maria T Diaz-Meco
- Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA
| | - Jorge Moscat
- Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
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49
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Brandl L, Zhang Y, Kirstein N, Sendelhofert A, Boos SL, Jung P, Greten F, Rad R, Menssen A. Targeting c-MYC through Interference with NAMPT and SIRT1 and Their Association to Oncogenic Drivers in Murine Serrated Intestinal Tumorigenesis. Neoplasia 2019; 21:974-988. [PMID: 31442917 PMCID: PMC6710297 DOI: 10.1016/j.neo.2019.07.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 07/23/2019] [Accepted: 07/23/2019] [Indexed: 12/13/2022] Open
Abstract
We recently described a positive feedback loop connecting c-MYC, NAMPT, DBC1 and SIRT1 that contributes to unrestricted cancer cell proliferation. Here we determine the relevance of the loop for serrated route intestinal tumorigenesis using genetically well-defined BrafV600E and K-rasG12D mouse models. In both models we show that c-MYC and SIRT1 protein expression increased through progression from hyperplasia to invasive carcinomas and metastases. It correlated with high NAMPT expression and was directly associated to activation of the oncogenic drivers. Assessing functional and molecular consequences of pharmacological interference with factors of the loop, we found that inhibition of NAMPT resulted in apoptosis and reduced clonogenic growth in human BRAF-mutant colorectal cancer cell lines and patient-derived tumoroids. Blocking SIRT1 activity was only effective when combined with a PI3K inhibitor, whereas the latter antagonized the effects of NAMPT inhibition. Interfering with the positive feedback loop was associated with down-regulation of c-MYC and temporary de-repression of TP53, explaining the anti-proliferative and pro-apoptotic effects. In conclusion we show that the c-MYC-NAMPT-DBC1-SIRT1 positive feedback loop contributes to murine serrated tumor progression. Targeting the feedback loop exerted a unique, dual therapeutic effect of oncoprotein inhibition and tumor suppressor activation. It may therefore represent a promissing target for serrated colorectal cancer, and presumably for other cancer types with deregulated c-MYC.
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Affiliation(s)
- Lydia Brandl
- Institute of Pathology, Ludwig-Maximilians University (LMU), Thalkirchnerstraße 36, 80337 Munich, Germany.
| | - Yina Zhang
- Institute of Pathology, Ludwig-Maximilians University (LMU), Thalkirchnerstraße 36, 80337 Munich, Germany; Research group "Signaling pathways in colorectal cancer"; German Cancer Consortium (DKTK), and German Cancer Research Center DKFZ, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
| | - Nina Kirstein
- Institute of Pathology, Ludwig-Maximilians University (LMU), Thalkirchnerstraße 36, 80337 Munich, Germany; Research group "Signaling pathways in colorectal cancer".
| | - Andrea Sendelhofert
- Institute of Pathology, Ludwig-Maximilians University (LMU), Thalkirchnerstraße 36, 80337 Munich, Germany.
| | - Sophie Luise Boos
- Institute of Pathology, Ludwig-Maximilians University (LMU), Thalkirchnerstraße 36, 80337 Munich, Germany; German Cancer Consortium (DKTK), and German Cancer Research Center DKFZ, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
| | - Peter Jung
- Institute of Pathology, Ludwig-Maximilians University (LMU), Thalkirchnerstraße 36, 80337 Munich, Germany; German Cancer Consortium (DKTK), and German Cancer Research Center DKFZ, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
| | - Florian Greten
- Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Paul-Ehrlich-Straße 42-44, 60596 Frankfurt/Main, Germany; Frankfurt Cancer Institute, Goethe University Frankfurt, 60596 Frankfurt/Main, Germany;and German Cancer Consortium (DKTK) and German Cancer Research Center DKFZ, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
| | - Roland Rad
- Institute of Molecular Oncology and Functional Genomics, School of Medicine, Technical University of Munich, Munich, Germany; Center for Translational Cancer Research (TranslaTUM), Technical University of Munich, Germany; Department of Medicine II, School of Medicine, Technical University of Munich, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
| | - Antje Menssen
- Institute of Pathology, Ludwig-Maximilians University (LMU), Thalkirchnerstraße 36, 80337 Munich, Germany; Research group "Signaling pathways in colorectal cancer"; German Cancer Consortium (DKTK), and German Cancer Research Center DKFZ, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
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50
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Guillon J, Petit C, Toutain B, Guette C, Lelièvre E, Coqueret O. Chemotherapy-induced senescence, an adaptive mechanism driving resistance and tumor heterogeneity. Cell Cycle 2019; 18:2385-2397. [PMID: 31397193 DOI: 10.1080/15384101.2019.1652047] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Senescence is activated in response to chemotherapy to prevent the propagation of cancer cells. In transformed cells, recent studies have shown that this response is not always definitive and that persistent populations can use senescence as an adaptive pathway to restart proliferation and become more aggressive. Here we discuss the results showing that an incomplete and heterogeneous senescence response plays a key role in chemotherapy resistance. Surviving to successive chemotherapy regimens, chronically existing senescent cells can create a survival niche through paracrine cooperations with neighboring cells. This favors chemotherapy escape of premalignant clones but might also allow the survival of adjacent clones presenting a lower fitness. A better characterization of senescence heterogeneity in transformed cells is therefore necessary. This will help us to understand this incomplete response to therapy and how it could generate clones with increased tumor capacity leading to disease relapse.
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Affiliation(s)
- Jordan Guillon
- Paul Papin ICO Cancer Center, CRCINA, INSERM, Université de Nantes, Université d'Angers , Angers , France.,SIRIC ILIAD , Nantes, Angers , France
| | - Coralie Petit
- Paul Papin ICO Cancer Center, CRCINA, INSERM, Université de Nantes, Université d'Angers , Angers , France.,SIRIC ILIAD , Nantes, Angers , France
| | - Bertrand Toutain
- Paul Papin ICO Cancer Center, CRCINA, INSERM, Université de Nantes, Université d'Angers , Angers , France.,SIRIC ILIAD , Nantes, Angers , France
| | - Catherine Guette
- Paul Papin ICO Cancer Center, CRCINA, INSERM, Université de Nantes, Université d'Angers , Angers , France.,SIRIC ILIAD , Nantes, Angers , France
| | - Eric Lelièvre
- Paul Papin ICO Cancer Center, CRCINA, INSERM, Université de Nantes, Université d'Angers , Angers , France.,SIRIC ILIAD , Nantes, Angers , France
| | - Olivier Coqueret
- Paul Papin ICO Cancer Center, CRCINA, INSERM, Université de Nantes, Université d'Angers , Angers , France.,SIRIC ILIAD , Nantes, Angers , France
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