TY - JOUR TI - Apc-mutant cells act as supercompetitors in intestinal tumour initiation AU - van Neerven, Sanne M. AU - de Groot, Nina E. AU - Nijman, Lisanne E. AU - Scicluna, Brendon P. AU - van Driel, Milou S. AU - Lecca, Maria C. AU - Warmerdam, Daniël O. AU - Kakkar, Vaishali AU - Moreno, Leandro F. AU - Vieira Braga, Felipe A. AU - Sanches, Delano R. AU - Ramesh, Prashanthi AU - ten Hoorn, Sanne AU - Aelvoet, Arthur S. AU - van Boxel, Marouska F. AU - Koens, Lianne AU - Krawczyk, Przemek M. AU - Koster, Jan AU - Dekker, Evelien AU - Medema, Jan Paul AU - Winton, Douglas J. AU - Bijlsma, Maarten F. AU - Morrissey, Edward AU - Léveillé, Nicolas AU - Vermeulen, Louis T2 - Nature AB - 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. DA - 2021/06/02/ PY - 2021 DO - 10.1038/s41586-021-03558-4 DP - www.nature.com SP - 1 EP - 6 LA - en SN - 1476-4687 UR - https://www.nature.com/articles/s41586-021-03558-4 Y2 - 2021/06/03/18:28:17 ER -