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NOTUM from Apc-mutant cells biases clonal competition to initiate cancer

التفاصيل البيبلوغرافية
العنوان: NOTUM from Apc-mutant cells biases clonal competition to initiate cancer
المؤلفون: Pirjo Nummela, Colin Nixon, William C. Clark, Ella Gilchrist, Simon J. Leedham, Michael C. Hodder, Nalle Pentinmikko, Arafath Kaja Najumudeen, Nathalie Sphyris, E. Yvonne Jones, Jean-Paul Vincent, Hans Clevers, Nicky J. Willis, Alexander Raven, Kristina Kirschner, Dustin J. Flanagan, Paul V. Fish, Emma Minnee, Pekka Katajisto, Ville Hietakangas, Owen J. Sansom, Christine Perret, Lynn McGarry, Nadia Nasreddin, Rachel A. Ridgway, Ann C. Williams, Kathryn Gilroy, Kalle Luopajärvi, Sandra Scharaw, Béatrice Romagnolo, Marianne Lähde, Ari Ristimäki, Johanna Englund, Anna Taylor Webb, Kari Alitalo, Ann Hedley
المساهمون: Hubrecht Institute for Developmental Biology and Stem Cell Research, Institute of Biotechnology (-2009), University of Helsinki, CAN-PRO - Translational Cancer Medicine Program, Centre of Excellence in Stem Cell Metabolism, Helsinki Institute of Life Science HiLIFE, Institute of Biotechnology, Juha Klefström / Principal Investigator, Research Programs Unit, Department of Pathology, Doctoral Programme in Biomedicine, ATG - Applied Tumor Genomics, Doctoral Programme in Integrative Life Science, HUSLAB, Kari Alitalo / Principal Investigator, Molecular and Integrative Biosciences Research Programme, Biosciences, Nutrient sensing laboratory
المصدر: Nature, 594(7863), 430-435. Nature Publishing Group
Flanagan, D J, Williams, A C, Katajisto, P K, Sampson, O J & al., E 2021, ' NOTUM from Apc-mutant cells biases clonal competition to initiate cancer ', Nature, vol. 594, pp. 430–435 (2021) . https://doi.org/10.1038/s41586-021-03525-z
سنة النشر: 2021
مصطلحات موضوعية: 0301 basic medicine, Male, HOMEOSTASIS, Cell, medicine.disease_cause, Cell Transformation, Inbred C57BL, Ligands, BETA-CATENIN, ACTIVATION, PATHWAY, Mice, 0302 clinical medicine, Conditioned, INTESTINE, Stem Cells/cytology, Wnt Signaling Pathway, Cell Competition/genetics, Esterases/antagonists & inhibitors, Mutation, Multidisciplinary, biology, Stem Cells, Cell Transformation, Neoplastic/genetics, Wnt signaling pathway, Esterases, Cell Differentiation, Neoplastic/genetics, Cell biology, Organoids, POLYPOSIS, medicine.anatomical_structure, Cell Transformation, Neoplastic, 030220 oncology & carcinogenesis, Disease Progression, Organoids/cytology, Female, Stem cell, Colorectal Neoplasms, STEM-CELLS, BONE-FORMATION, Adenoma, Beta-catenin, Genes, APC, 3122 Cancers, Crypt, Adenomatous Polyposis Coli Protein, WNT, 03 medical and health sciences, Cancer stem cell, Wnt Proteins/metabolism, medicine, Animals, Humans, Adenomatous Polyposis Coli Protein/genetics, Cell Proliferation, Adenoma/genetics, Colorectal Neoplasms/genetics, Notum, Culture Media, APC, Wnt Proteins, Mice, Inbred C57BL, 030104 developmental biology, Genes, Cell Competition, Culture Media, Conditioned, biology.protein, 1182 Biochemistry, cell and molecular biology
الوصف: Funding Information: Acknowledgements We thank the Core Services and Advanced Technologies at the Cancer Research UK Beatson Institute (C596/A17196 and A31287), and particularly the Biological Services Unit, Histology Service and Molecular Technologies; members of the Sansom and Katajisto laboratories for discussions of the data and manuscript; and BRC Oxford for supplying patient material. O.J.S. and his laboratory members were supported by Cancer Research UK (A28223, A21139, A12481 and A17196). D.J.F. and M.C.H. were supported by the UK Medical Research Council (MR/R017247/1 and MR/J50032X/1, respectively). SpecifiCancer CRUK Grand Challenge (C7932/A29055) is funded by Cancer Research UK and the Mark Foundation for Cancer Research. P.K. and his laboratory members were supported by the Academy of Finland Centre of Excellence MetaStem (266869, 304591 and 320185), the ERC Starting Grant 677809, the Swedish Research Council 2018-03078, the Cancerfonden 190634, the Jane and Aatos Erkko Foundation and the Cancer Foundation Finland. N.P. was supported by the Finnish Cultural Foundation, the Biomedicum Helsinki Foundation, the Orion Research Foundation sr and The Paulo Foundation. P.V.F. was supported by Alzheimer’s Research UK and The Francis Crick Institute. The ARUK UCL Drug Discovery Institute receives its core funding from Alzheimer’s Research UK (520909). The Francis Crick Institute receives its core funding from Cancer Research UK (FC001002), the UK Medical Research Council (FC001002) and the Wellcome Trust (FC001002). Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature Limited. The tumour suppressor APC is the most commonly mutated gene in colorectal cancer. Loss of Apc in intestinal stem cells drives the formation of adenomas in mice via increased WNT signalling(1), but reduced secretion of WNT ligands increases the ability of Apc-mutant intestinal stem cells to colonize a crypt (known as fixation)(2). Here we investigated how Apc-mutant cells gain a clonal advantage over wild-type counterparts to achieve fixation. We found that Apc-mutant cells are enriched for transcripts that encode several secreted WNT antagonists, with Notum being the most highly expressed. Conditioned medium from Apc-mutant cells suppressed the growth of wild-type organoids in a NOTUM-dependent manner. Furthermore, NOTUM-secreting Apc-mutant clones actively inhibited the proliferation of surrounding wild-type crypt cells and drove their differentiation, thereby outcompeting crypt cells from the niche. Genetic or pharmacological inhibition of NOTUM abrogated the ability of Apc-mutant cells to expand and form intestinal adenomas. We identify NOTUM as a key mediator during the early stages of mutation fixation that can be targeted to restore wild-type cell competitiveness and provide preventative strategies for people at a high risk of developing colorectal cancer.
وصف الملف: application/pdf
اللغة: English
تدمد: 0028-0836
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d5733edf6d5fc44fd62aea7978eb694e
https://pure.knaw.nl/portal/en/publications/69a3582f-fc29-4f40-bc5f-17ba7825a11a
حقوق: OPEN
رقم الأكسشن: edsair.doi.dedup.....d5733edf6d5fc44fd62aea7978eb694e
قاعدة البيانات: OpenAIRE
الوصف
تدمد:00280836