RNF43 mutations facilitate mucinous colorectal cancer metastasis via formation of a tumour-intrinsic niche
Bugter, J. M.; El Bouazzaoui, L.; Kucukkose, E.; Hong, Y.; Sprangers, J.; Jordens, I.; Fenderico, N.; Gonzalez, D. M.; van Boxtel, R.; Suijkerbuijk, S. J. E.; Tejpar, S.; Snippert, H. J. G.; Kranenburg, O.; Maurice, M. M.
Show abstract
In colorectal cancer (CRC), RNF43 mutations are linked to BRAF V600E-initiated serrated adenomas that advance into mucinous adenocarcinomas with poor prognosis upon metastasis. How RNF43 mutations facilitate a metastasis-prone growth state remains unknown. Here, we addressed this issue by repairing mutant RNF43 in patient-derived BRAF-mutant CRC organoids using gene editing. Upon RNF43 correction, 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 in RNF43, but not APC. In patient samples, enhanced TINC profiles correlate with RNF43-mutant CRC, mucinous histology and metastatic disease, thus representing a general cellular mechanism by which tumours acquire a self-sufficient, pro-metastatic growth state.
Matching journals
The top 5 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Dictionary of human intestinal organoid responses to secreted niche factors at single cell resolution 97%
- p53 mutation in normal esophagus promotes multiple stages of carcinogenesis but is constrained by clonal competition 97%
- Reconstructing disease dynamics for mechanistic insights and clinical benefit 96%
Similar papers in this journal
Similar papers in this journal
- The neuroendocrine transition in prostate cancer is dynamic and dependent on ASCL1 96%
- Global loss of promoter-enhancer connectivity and rebalancing of gene expression during early colorectal cancer carcinogenesis 96%
- Multi-modal digital pathology for colorectal cancer diagnosis by high-plex immunofluorescence imaging and traditional histology of the same tissue section 95%
Similar papers in this journal
- Niche-driven phenotypic plasticity and cis-regulatory dynamics of a revised model for intestinal secretory differentiation 97%
- Molecular phenotyping of colorectal neoplasia shows dynamic and adaptive cancer stem cell population admixture 95%
- An organoid co-culture model for probing systemic anti-tumor immunity in lung cancer 95%
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.