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

Colorectal cancer (CRC) develops via two mutually exclusive genetic pathways that involve distinct WNT pathway alterations. Downstream APC mutations initiate development of conventional WNT-high adenocarcinomas. By contrast, RNF43 mutations induce hypersensitivity to WNTs at the receptor level and are mainly found in BRAF V600E-initiated serrated adenomas that advance into WNT-low mucinous adenocarcinomas with poor prognosis upon metastasis. How RNF43 mutations contribute to tumour progression remains unclear. Here, we employed gene editing to repair RNF43 mutations in patient-derived CRC organoids. In comparison to their RNF43-mutant counterparts, RNF43-corrected CRC organoids display a diminished mucinous phenotype, loss of niche factor independency and loss of metastatic capacity upon orthotopic transplantation in mice. Mechanistically, mutant RNF43 promotes formation of a non-dividing secretory cell population that secretes essential growth factors and provide a state of self-sufficiency to the cancer epithelium. Unlike APC mutations, we show that RNF43-mutations provide tuneable WNT levels that permits the formation of these niche-like cells in parallel to proliferative WNT-high cancer cells. Also in patient samples, formation of these tumour-intrinsic niche cells (TINCs) correlate with RNF43-mutant CRC, mucinous histology and metastatic capacity and represents a cellular mechanism by which tumours acquire self-sufficiency. ### Competing Interest Statement Madelon Maurice is cofounder and shareholder of Laigo Bio B.V. The other authors declare no competing interests.