Polyclonality overcomes fitness barriers in Apc-driven tumorigenesis

Iannish D. Sadien, Sam Adler, Shenay Mehmed, Sasha Bailey, Ashley Sawle, Dominique-Laurent Couturier, Matthew Eldridge, David J. Adams, Richard Kemp, Filipe C. Lourenço and Douglas J. Winton ()
Additional contact information
Iannish D. Sadien: Li Ka Shing Centre
Sam Adler: Li Ka Shing Centre
Shenay Mehmed: Li Ka Shing Centre
Sasha Bailey: The Francis Crick Institute
Ashley Sawle: Li Ka Shing Centre
Dominique-Laurent Couturier: Li Ka Shing Centre
Matthew Eldridge: Li Ka Shing Centre
David J. Adams: Wellcome Trust Genome Campus, Hinxton
Richard Kemp: Li Ka Shing Centre
Filipe C. Lourenço: Li Ka Shing Centre
Douglas J. Winton: Li Ka Shing Centre

Nature, 2024, vol. 634, issue 8036, 1196-1203

Abstract: Abstract Loss-of-function mutations in the tumour suppressor APC are an initial step in intestinal tumorigenesis1,2. 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 mutants3–5. Reports of polyclonal intestinal tumours in human patients and mouse models appear at odds with this process6,7. 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.

Date: 2024
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DOI: 10.1038/s41586-024-08053-0

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