biostudies-literatureUnknown634(8036)Sadien IDLoss-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 paNature1196-1203https://www.ebi.ac.uk/biostudies/studies/S-EPMC11525183biostudies-literaturePolyclonality overcomes fitness barriers in Apc-driven tumorigenesis.PMC11525183Sadien IDBailey SCouturier DLAdler SKemp RLourenco FCAdams DJWinton DJMehmed SSawle AEldridge MfalsePolyclonality overcomes fitness barriers in Apc-driven tumorigenesis.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 pa2024-01-01T00:00:00Z2024 Oct2026-07-16T03:08:28.514Z2025-04-06T15:31:57.443ZS-EPMC115251833947820610.1038/s41586-024-08053-0