Polyclonality overcomes fitness barriers in Apc-driven tumorigenesis.

Autor: Sadien ID; Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK., Adler S; Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK., Mehmed S; Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK., Bailey S; Tumour Cell Biology Laboratory, The Francis Crick Institute, London, UK., Sawle A; Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK., Couturier DL; Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK., Eldridge M; Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK., Adams DJ; Wellcome Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK., Kemp R; Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK., Lourenço FC; Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK., Winton DJ; Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK. doug.winton@cruk.cam.ac.uk.
Jazyk: angličtina
Zdroj: Nature [Nature] 2024 Oct; Vol. 634 (8036), pp. 1196-1203. Date of Electronic Publication: 2024 Oct 30.
DOI: 10.1038/s41586-024-08053-0
Abstrakt: Loss-of-function mutations in the tumour suppressor APC are an initial step in intestinal tumorigenesis 1,2 . APC-mutant intestinal stem cells outcompete their wild-type neighbours through the secretion of Wnt antagonists, which accelerates the fixation and subsequent rapid clonal expansion of mutants 3-5 . Reports of polyclonal intestinal tumours in human patients and mouse models appear at odds with this process 6,7 . Here we combine multicolour lineage tracing with chemical mutagenesis in mice to show that a large proportion of intestinal tumours have a multiancestral origin. Polyclonal tumours retain a structure comprising subclones with distinct Apc mutations and transcriptional states, driven predominantly by differences in KRAS and MYC signalling. These pathway-level changes are accompanied by profound differences in cancer stem cell phenotypes. Of note, these findings are confirmed by introducing an oncogenic Kras mutation that results in predominantly monoclonal tumour formation. Further, polyclonal tumours have accelerated growth dynamics, suggesting a link between polyclonality and tumour progression. Together, these findings demonstrate the role of interclonal interactions in promoting tumorigenesis through non-cell autonomous pathways that are dependent on the differential activation of oncogenic pathways between clones.
(© 2024. The Author(s).)
Databáze: MEDLINE
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