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

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 () and Owen J. Sansom ()
Additional contact information
Dustin J. Flanagan: Cancer Research UK Beatson Institute
Nalle Pentinmikko: University of Helsinki
Kalle Luopajärvi: University of Helsinki
Nicky J. Willis: University College London
Kathryn Gilroy: Cancer Research UK Beatson Institute
Alexander P. Raven: Cancer Research UK Beatson Institute
Lynn Mcgarry: Cancer Research UK Beatson Institute
Johanna I. Englund: University of Helsinki
Anna T. Webb: Karolinska Institutet
Sandra Scharaw: Karolinska Institutet
Nadia Nasreddin: University of Oxford
Michael C. Hodder: Cancer Research UK Beatson Institute
Rachel A. Ridgway: Cancer Research UK Beatson Institute
Emma Minnee: Cancer Research UK Beatson Institute
Nathalie Sphyris: Cancer Research UK Beatson Institute
Ella Gilchrist: Cancer Research UK Beatson Institute
Arafath K. Najumudeen: Cancer Research UK Beatson Institute
Beatrice Romagnolo: Université de Paris, Institut Cochin, INSERM, CNRS
Christine Perret: Université de Paris, Institut Cochin, INSERM, CNRS
Ann C. Williams: University of Bristol
Hans Clevers: Harvard Medical School
Pirjo Nummela: University of Helsinki and Helsinki University Hospital
Marianne Lähde: University of Helsinki
Kari Alitalo: University of Helsinki
Ville Hietakangas: University of Helsinki
Ann Hedley: Cancer Research UK Beatson Institute
William Clark: Cancer Research UK Beatson Institute
Colin Nixon: Cancer Research UK Beatson Institute
Kristina Kirschner: University of Glasgow
E. Yvonne Jones: University of Oxford
Ari Ristimäki: University of Helsinki and Helsinki University Hospital
Simon J. Leedham: University of Oxford
Paul V. Fish: University College London
Jean-Paul Vincent: The Francis Crick Institute
Pekka Katajisto: University of Helsinki
Owen J. Sansom: Cancer Research UK Beatson Institute

Nature, 2021, vol. 594, issue 7863, 430-435

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-021-03525-z

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