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

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.
Authors	Dustin J Flanagan, Nalle Pentinmikko, Kalle Luopajärvi, Nicky J Willis, Kathryn Gilroy, Alexander P Raven, Lynn Mcgarry, Johanna I Englund, Anna T Webb, Sandra Scharaw, Nadia Nasreddin, Michael C Hodder, Rachel A Ridgway, Emma Minnee, Nathalie Sphyris, Ella Gilchrist, Arafath K Najumudeen, Beatrice Romagnolo, Christine Perret, Ann C Williams, Hans Clevers, Pirjo Nummela, Marianne Lähde, Kari Alitalo, Ville Hietakangas, Ann Hedley, William Clark, Colin Nixon, Kristina Kirschner, E Yvonne Jones, Ari Ristimäki, Simon J Leedham, Paul V Fish, Jean-Paul Vincent, Pekka Katajisto, Owen J Sansom
Journal	Nature (Nature) Vol. 594 Issue 7863 Pg. 430-435 (06 2021) ISSN: 1476-4687 [Electronic] England
PMID	34079124 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Adenomatous Polyposis Coli Protein Culture Media, Conditioned Ligands Wnt Proteins adenomatous polyposis coli protein, mouse Esterases Notum protein, human Notum protein, mouse
Topics	Adenoma (genetics, pathology) Adenomatous Polyposis Coli Protein (genetics) Animals Cell Competition (genetics) Cell Differentiation Cell Proliferation Cell Transformation, Neoplastic (genetics) Colorectal Neoplasms (genetics, pathology) Culture Media, Conditioned Disease Progression Esterases (antagonists & inhibitors, genetics, metabolism) Female Genes, APC Humans Ligands Male Mice Mice, Inbred C57BL Mutation Organoids (cytology, metabolism, pathology) Stem Cells (cytology, metabolism) Wnt Proteins (metabolism) Wnt Signaling Pathway

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