Apc-mutant cells act as supercompetitors in intestinal tumour initiation.

Autor: van Neerven SM; Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, Amsterdam, The Netherlands.; Oncode Institute, Amsterdam, The Netherlands., de Groot NE; Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, Amsterdam, The Netherlands.; Oncode Institute, Amsterdam, The Netherlands., Nijman LE; Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, Amsterdam, The Netherlands.; Oncode Institute, Amsterdam, The Netherlands., Scicluna BP; Center for Experimental Molecular Medicine, Amsterdam Infection & Immunity, Amsterdam UMC, Amsterdam, The Netherlands.; Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam UMC, Amsterdam, The Netherlands., van Driel MS; Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, Amsterdam, The Netherlands.; Oncode Institute, Amsterdam, The Netherlands., Lecca MC; Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, Amsterdam, The Netherlands.; Oncode Institute, Amsterdam, The Netherlands., Warmerdam DO; Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, Amsterdam, The Netherlands.; Oncode Institute, Amsterdam, The Netherlands.; CRISPR Platform, University of Amsterdam, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands., Kakkar V; Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, Amsterdam, The Netherlands.; Oncode Institute, Amsterdam, The Netherlands., Moreno LF; Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, Amsterdam, The Netherlands.; Oncode Institute, Amsterdam, The Netherlands., Vieira Braga FA; Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, Amsterdam, The Netherlands.; Oncode Institute, Amsterdam, The Netherlands., Sanches DR; Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, Amsterdam, The Netherlands.; Oncode Institute, Amsterdam, The Netherlands., Ramesh P; Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, Amsterdam, The Netherlands.; Oncode Institute, Amsterdam, The Netherlands., Ten Hoorn S; Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, Amsterdam, The Netherlands.; Oncode Institute, Amsterdam, The Netherlands., Aelvoet AS; Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, Amsterdam, The Netherlands., van Boxel MF; Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, Amsterdam, The Netherlands.; Oncode Institute, Amsterdam, The Netherlands., Koens L; Department of Pathology, Amsterdam University Medical Centers, Amsterdam, The Netherlands., Krawczyk PM; Department of Medical Biology, Amsterdam University Medical Centers, Amsterdam, The Netherlands., Koster J; Department of Oncogenomics, Amsterdam University Medical Centers, Amsterdam, The Netherlands., Dekker E; Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, Amsterdam, The Netherlands., Medema JP; Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, Amsterdam, The Netherlands.; Oncode Institute, Amsterdam, The Netherlands., Winton DJ; Cancer Research UK, Cambridge Institute, University of Cambridge, Cambridge, UK., Bijlsma MF; Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, Amsterdam, The Netherlands.; Oncode Institute, Amsterdam, The Netherlands., Morrissey E; MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK., Léveillé N; Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, Amsterdam, The Netherlands.; Oncode Institute, Amsterdam, The Netherlands., Vermeulen L; Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, Amsterdam, The Netherlands. l.vermeulen@amsterdamumc.nl.; Oncode Institute, Amsterdam, The Netherlands. l.vermeulen@amsterdamumc.nl.
Jazyk: angličtina
Zdroj: Nature [Nature] 2021 Jun; Vol. 594 (7863), pp. 436-441. Date of Electronic Publication: 2021 Jun 02.
DOI: 10.1038/s41586-021-03558-4
Abstrakt: A delicate equilibrium of WNT agonists and antagonists in the intestinal stem cell (ISC) niche is critical to maintaining the ISC compartment, as it accommodates the rapid renewal of the gut lining. Disruption of this balance by mutations in the tumour suppressor gene APC, which are found in approximately 80% of all human colon cancers, leads to unrestrained activation of the WNT pathway 1,2 . It has previously been established that Apc-mutant cells have a competitive advantage over wild-type ISCs 3 . Consequently, Apc-mutant ISCs frequently outcompete all wild-type stem cells within a crypt, thereby reaching clonal fixation in the tissue and initiating cancer formation. However, whether the increased relative fitness of Apc-mutant ISCs involves only cell-intrinsic features or whether Apc mutants are actively involved in the elimination of their wild-type neighbours remains unresolved. Here we show that Apc-mutant ISCs function as bona fide supercompetitors by secreting WNT antagonists, thereby inducing differentiation of neighbouring wild-type ISCs. Lithium chloride prevented the expansion of Apc-mutant clones and the formation of adenomas by rendering wild-type ISCs insensitive to WNT antagonists through downstream activation of WNT by inhibition of GSK3β. Our work suggests that boosting the fitness of healthy cells to limit the expansion of pre-malignant clones may be a powerful strategy to limit the formation of cancers in high-risk individuals.
Databáze: MEDLINE
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