NOTUM from Apc-mutant cells biases clonal competition to initiate cancer

Nature. 2021 Jun;594(7863):430-435. doi: 10.1038/s41586-021-03525-z. Epub 2021 Jun 2.

Abstract

The tumour suppressor APC is the most commonly mutated gene in colorectal cancer. Loss of Apc in intestinal stem cells drives the formation of adenomas in mice via increased WNT signalling1, but reduced secretion of WNT ligands increases the ability of Apc-mutant intestinal stem cells to colonize a crypt (known as fixation)2. Here we investigated how Apc-mutant cells gain a clonal advantage over wild-type counterparts to achieve fixation. We found that Apc-mutant cells are enriched for transcripts that encode several secreted WNT antagonists, with Notum being the most highly expressed. Conditioned medium from Apc-mutant cells suppressed the growth of wild-type organoids in a NOTUM-dependent manner. Furthermore, NOTUM-secreting Apc-mutant clones actively inhibited the proliferation of surrounding wild-type crypt cells and drove their differentiation, thereby outcompeting crypt cells from the niche. Genetic or pharmacological inhibition of NOTUM abrogated the ability of Apc-mutant cells to expand and form intestinal adenomas. We identify NOTUM as a key mediator during the early stages of mutation fixation that can be targeted to restore wild-type cell competitiveness and provide preventative strategies for people at a high risk of developing colorectal cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoma / genetics
  • Adenoma / pathology
  • Adenomatous Polyposis Coli Protein / genetics
  • Animals
  • Cell Competition* / genetics
  • Cell Differentiation
  • Cell Proliferation
  • Cell Transformation, Neoplastic* / genetics
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology*
  • Culture Media, Conditioned
  • Disease Progression
  • Esterases / antagonists & inhibitors
  • Esterases / genetics
  • Esterases / metabolism*
  • Female
  • Genes, APC*
  • Humans
  • Ligands
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mutation*
  • Organoids / cytology
  • Organoids / metabolism
  • Organoids / pathology
  • Stem Cells / cytology
  • Stem Cells / metabolism
  • Wnt Proteins / metabolism
  • Wnt Signaling Pathway

Substances

  • Adenomatous Polyposis Coli Protein
  • Culture Media, Conditioned
  • Ligands
  • Wnt Proteins
  • adenomatous polyposis coli protein, mouse
  • Esterases
  • Notum protein, human
  • Notum protein, mouse