Apc-mutant cells act as supercompetitors in intestinal tumour initiation

Sanne M. van Neerven, Nina E. de Groot, Lisanne E. Nijman, Brendon P. Scicluna, Milou S. van Driel, Maria C. Lecca, Daniël O. Warmerdam, Vaishali Kakkar, Leandro F. Moreno, Felipe A. Vieira Braga, Delano R. Sanches, Prashanthi Ramesh, Sanne ten Hoorn, Arthur S. Aelvoet, Marouska F. van Boxel, Lianne Koens, Przemek M. Krawczyk, Jan Koster, Evelien Dekker, Jan Paul Medema, Douglas J. Winton, Maarten F. Bijlsma, Edward Morrissey, Nicolas Léveillé and Louis Vermeulen ()
Additional contact information
Sanne M. van Neerven: Amsterdam University Medical Centers
Nina E. de Groot: Amsterdam University Medical Centers
Lisanne E. Nijman: Amsterdam University Medical Centers
Brendon P. Scicluna: Amsterdam Infection & Immunity, Amsterdam UMC
Milou S. van Driel: Amsterdam University Medical Centers
Maria C. Lecca: Amsterdam University Medical Centers
Daniël O. Warmerdam: Amsterdam University Medical Centers
Vaishali Kakkar: Amsterdam University Medical Centers
Leandro F. Moreno: Amsterdam University Medical Centers
Felipe A. Vieira Braga: Amsterdam University Medical Centers
Delano R. Sanches: Amsterdam University Medical Centers
Prashanthi Ramesh: Amsterdam University Medical Centers
Sanne ten Hoorn: Amsterdam University Medical Centers
Arthur S. Aelvoet: Amsterdam University Medical Centers
Marouska F. van Boxel: Amsterdam University Medical Centers
Lianne Koens: Amsterdam University Medical Centers
Przemek M. Krawczyk: Amsterdam University Medical Centers
Jan Koster: Amsterdam University Medical Centers
Evelien Dekker: Amsterdam University Medical Centers
Jan Paul Medema: Amsterdam University Medical Centers
Douglas J. Winton: University of Cambridge
Maarten F. Bijlsma: Amsterdam University Medical Centers
Edward Morrissey: University of Oxford, John Radcliffe Hospital
Nicolas Léveillé: Amsterdam University Medical Centers
Louis Vermeulen: Amsterdam University Medical Centers

Nature, 2021, vol. 594, issue 7863, 436-441

Abstract: Abstract A delicate equilibrium of WNT agonists and antagonists in the intestinal stem cell (ISC) niche is critical to maintaining the ISC compartment, as it accommodates the rapid renewal of the gut lining. Disruption of this balance by mutations in the tumour suppressor gene APC, which are found in approximately 80% of all human colon cancers, leads to unrestrained activation of the WNT pathway1,2. It has previously been established that Apc-mutant cells have a competitive advantage over wild-type ISCs3. Consequently, Apc-mutant ISCs frequently outcompete all wild-type stem cells within a crypt, thereby reaching clonal fixation in the tissue and initiating cancer formation. However, whether the increased relative fitness of Apc-mutant ISCs involves only cell-intrinsic features or whether Apc mutants are actively involved in the elimination of their wild-type neighbours remains unresolved. Here we show that Apc-mutant ISCs function as bona fide supercompetitors by secreting WNT antagonists, thereby inducing differentiation of neighbouring wild-type ISCs. Lithium chloride prevented the expansion of Apc-mutant clones and the formation of adenomas by rendering wild-type ISCs insensitive to WNT antagonists through downstream activation of WNT by inhibition of GSK3β. Our work suggests that boosting the fitness of healthy cells to limit the expansion of pre-malignant clones may be a powerful strategy to limit the formation of cancers in high-risk individuals.

Date: 2021
References: Add references at CitEc
Citations: View citations in EconPapers (2)

Downloads: (external link)
https://www.nature.com/articles/s41586-021-03558-4 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:594:y:2021:i:7863:d:10.1038_s41586-021-03558-4

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-021-03558-4

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().