Manuel Mastel, Aitana Guiseris Martinez, Umberto Pozza, Jasmin Meier, Ioannis Chiotakakos, Sandra Jaun, Carolin Artmann, Gabriele Diamante, Nikolaos Georgakopoulos, Philipp Albrecht, Yvonne Petersen, Saskia Reuter, Barbara Schmitt, Michael Günther, Alexandra Thiran, Istiffa Nurfauziah, Ian Ghezzi, Kyanna S Ouyang, Michael D Milsom, Jens Puschhof, Nic G Reitsam, Kim E Boonekamp, Johannes Betge, Steffen Ormanns, Michael Boutros, Rene Jackstadt
WNT pathway activation is a critical determinant of malignant transformation in BRAF-mutant MSS CRC by enabling immune escape. These findings identify WNT signaling as a central regulator of tumor-immune interactions and a potential therapeutic target in this aggressive CRC subtype.
BACKGROUND & AIMS: BRAF-mutant colorectal cancer (CRC) is a clinically aggressive subtype arising from the serrated pathway and is associated with poor prognosis and therapy resistance. The mechanisms driving malignant transformation in microsatellite-stable (MSS) BRAF-mutant CRC remain incompletely understood. We aimed to define the role of WNT pathway activation in serrated CRC progression and tumor-immune interactions.
METHODS: We generated multiple genetically engineered mouse models (GEMMs) of BRAF-mutant MSS CRC and complementary organoid-based transplantation models. Genetic alterations in WNT pathway components were functionally interrogated. Tumor development and immune microenvironment remodeling were analyzed using bulk RNA sequencing, single-cell RNA sequencing, CITE-seq, and functional in vivo assays.
RESULTS: WNT pathway activation via APC or CTNNB1 mutations, but not RNF43 loss, was required for tumor initiation in BRAF-mutant CRC models. WNT activation induced a molecular subtype shift and suppressed immune response pathways. Mechanistically, WNT signaling suppressed CCL20 expression and remodeled the tumor microenvironment (TME) by promoting immunosuppressive myeloid populations and altering T-cell states. Functional assays demonstrated that WNT activation enhances tumor progression in immunocompetent settings, indicating immune evasion as a key driver of malignant progression.
CONCLUSIONS: WNT pathway activation is a critical determinant of malignant transformation in BRAF-mutant MSS CRC by enabling immune escape. These findings identify WNT signaling as a central regulator of tumor-immune interactions and a potential therapeutic target in this aggressive CRC subtype.