RNF43 mutations facilitate colorectal cancer metastasis via formation of a tumour-intrinsic niche

Abstract

SummaryIn colorectal cancer (CRC),RNF43mutations are linked to BRAF V600E-initiated serrated adenomas that advance into mucinous adenocarcinomas with poor prognosis upon metastasis. HowRNF43mutations facilitate a metastasis-prone growth state remains unknown. Here, we addressed this issue by repairing mutantRNF43in patient-derived BRAF-mutant CRC organoids using gene editing. UponRNF43correction, CRC organoids exhibit strongly decreased mucus production and, moreover, display loss of niche factor independence and metastatic capacity upon orthotopic transplantation in mice. Mechanistically, we show that mutant RNF43 promotes cancer cell lineage specification towards a non-dividing niche population that secretes essential growth factors, providing a state of self-sufficiency to the cancer epithelium. We show that phenotypic diversification into tumour-intrinsic niche cells (TINCs) and proliferative cancer stem cells depends on tuneable WNT levels enabled by mutations inRNF43, but notAPC. In patient samples, enhanced TINC profiles correlate withRNF43-mutant CRC, mucinous histology and metastatic disease, thus representing a general cellular mechanism by which tumours acquire a self-sufficient, pro-metastatic growth state.