Reverse-engineering metastatic colorectal cancer organoids reveals driver role of RNF43 mutation
A universal feature of colorectal cancer (CRC) is mutational deregulation of WNT signaling. Mutations in WNT pathway tumour suppressor RNF43 correlate with poor prognosis in metastatic CRC. We reverse-engineered RNF43 mutant patient-derived CRC organoids by correcting the RNF43 mutations back to wildtype using CRISPR-cas9. Using these new models we study how RNF43 mutations drive cancer development by evaluating in vivo tumorigenic and metastatic capacity, in vitro niche dependency, transcriptome and proteome changes, and drug sensitivity.