Polyclonality overcomes fitness barriers in Apc-driven tumorigenesis.

ABSTRACT: 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 pa

SUBMITTER: Sadien ID 

PROVIDER: S-EPMC11525183 | biostudies-literature | 2024 Oct

REPOSITORIES: biostudies-literature