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

Abstract

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.

Novel drug resistance mechanisms and drug targets in BRAF-mutated peritoneal metastasis from colorectal cancer

“…In vitro , BRAF mutations have been connected to enhanced ability of migration and invasion of CRC cell lines [ 39 ]. RNF43 mutations have also been associated with aggressive tumor biology, and in BRAF mutated patient derived organoids, RNF43 mutations were recently suggested to have a key role in promoting metastasis in animal models [ 40 , 41 ]. Taken together, the marked differences between the metastatic sites with high abundance of BRAF and RNF43 mutations in PM may contribute to explain the inferior survival in PM-CRC.…”