Apc-mutant cells act as supercompetitors in intestinal tumour initiation

Sanne van Neerven1,2, Nina E de Groot1,2, Lisanne E Nijman1,2, Brendon P Scicluna3,4, Milou S van Driel1,2, Maria C Lecca1,2, Daniël O Warmerdam1,2,5, Vaishali Kakkar1,2, Leandro F Moreno1,2, Felipe A Vieira Braga1,2, Delano R Sanches1,2, Prashanthi Ramesh1,2, Sanne Ten Hoorn1,2, Arthur S Aelvoet6, Marouska F van Boxel1,2, Lianne Koens7, Przemek M Krawczyk8, Jan Koster9, Evelien Dekker6, Jan Paul Medema1,2, Douglas J Winton10, Maarten F Bijlsma1,2, Edward Morrissey11, Nicolas Léveillé1,2, Louis Vermeulen12,13

  1. Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, Amsterdam, The Netherlands.
  2. Oncode Institute, Amsterdam, The Netherlands.
  3. Center for Experimental Molecular Medicine, Amsterdam Infection & Immunity, Amsterdam UMC, Amsterdam, The Netherlands.
  4. Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam UMC, Amsterdam, The Netherlands.
  5. CRISPR Platform, University of Amsterdam, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands.
  6. Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, Amsterdam, The Netherlands.
  7. Department of Pathology, Amsterdam University Medical Centers, Amsterdam, The Netherlands.
  8. Department of Medical Biology, Amsterdam University Medical Centers, Amsterdam, The Netherlands.
  9. Department of Oncogenomics, Amsterdam University Medical Centers, Amsterdam, The Netherlands.
  10. Cancer Research UK, Cambridge Institute, University of Cambridge, Cambridge, UK.
  11. MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
  12. Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, Amsterdam, The Netherlands. l.vermeulen@amsterdamumc.nl.
  13. Oncode Institute, Amsterdam, The Netherlands. l.vermeulen@amsterdamumc.nl.

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.

Presented By Sanne van Neerven | ORCID iD

Cancer BiologyNicholas Liao2021-06 (Jun)