WNT-driven immune evasion promotes malignant transformation of BRAF-mutant colorectal cancer
Mastel, M.; Martinez, A. G.; Pozza, U.; Meier, J.; Chiotakakos, I.; Jaun, S.; Diamante, G.; Georgakopoulos, N.; Albrecht, P.; Petersen, Y.; Reuter, S.; Schmitt, B.; Guenther, M.; Nurfauziah, I.; Ghezzi, I.; Ouyang, K. S.; Milsom, M.; Puschhof, J.; Reitsam, N. G.; Boonekamp, K. E.; Betge, J.; Ormanns, S.; Boutros, M.; Jackstadt, R.
Show abstract
BRAF-mutant colorectal cancer (CRC) constitutes a molecularly and clinically distinct subtype with poor prognosis and resistance to standard therapies, representing a major unmet clinical need. Arising from the serrated pathway of colorectal carcinogenesis rather than the classical adenoma-carcinoma sequence, this subgroup remains relatively understudied yet displays a more aggressive disease course. To investigate the progression of serrated CRC, we generated multiple genetically engineered mouse models (GEMMs) of BRAF-mutant, microsatellite-stable (MSS) CRC that closely recapitulate human disease. Our findings demonstrate that WNT-pathway activation via APC- or CTNNB1-mutations, but not RNF43-loss, initiates serrated CRC by suppressing immune-mediated tumor surveillance. Mechanistically, WNT-signaling drives distinct alterations in T cell phenotypes within the tumor microenvironment, enabling tumor progression. Together, these data indicate that WNT-signaling mediates immune escape during the malignant transformation of BRAF-mutant CRC.
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