Abstract Background: The WNT-β-catenin-APC signaling axis is the most mutated pathway in colorectal cancer (CRC). Two of the most commonly lost proteins in early colorectal tumorigenesis are the hormone ligands (guanylin and uroguanylin) for the tumor suppressor, guanylate cyclase 2C (GUCY2C). CRC tumorigenesis typically retains expression of GUCY2C, a transmembrane receptor expressed on the apical-lumen-facing surface of intestinal epithelial cells. Previously, we demonstrated that in CRC, activated WNT/β-catenin suppresses GUCY2C hormone expression, revealing an often-overlooked paradigm in which WNT/β-catenin signaling silences gene expression to promote CRC tumorigenesis. Results: Using four CRC lines with inducible WNT/β-catenin suppression, we found that WNT/β-catenin signaling reduces phosphorylation and activation of p38, a known tumor suppressor in CRC. We show, using both pharmacological and genetic approaches, that WNT/β-catenin-mediated inactivation of p38 is responsible for the loss of GUCY2C hormone expression. Additionally, p38 inactivation downstream of WNT/β-catenin accounts for the suppression of at least two-thirds of the genes repressed by WNT/β-catenin signaling. These studies identify a previously unrecognized gene set controlled by WNT/β-catenin via suppression of p38 activation. Next, we sought to identify the link between the WNT/β-catenin pathway and p38. Indeed, WNT/β-catenin signaling suppresses p38 activity through a MAPK-dependent mechanism, and inactivation of WNT/β-catenin increases MAP2K phosphorylation, while MAP2K3 knockdown mimics the effects of eliminating p38 on guanylin expression. In that context, phosphorylation of MAP2K is reduced in CRC tumors, compared to normal tissue, further supporting a role for this mechanism in CRC tumorigenesis. Conclusions: Our findings demonstrate that the WNT/β-catenin signaling pathway induces the expression of tumor promoters while also inducing broad gene suppression. Our results reveal broad intracellular signaling changes that occur during early CRC tumorigenesis following WNT/β-catenin mutations, providing mechanistic insight into both early CRC tumorigenesis and normal intestinal homeostasis. By elucidating these mechanisms, we can identify signaling pathways to restore guanylin and uroguanylin expression, reactivate GUCY2C, and reprogram gene expression disrupted by aberrant WNT/β-catenin signaling. In turn, this approach can provide novel strategies to prevent and treat colorectal cancer. Citation Format: Andrew E. Evans, Ariana A. Entezari, Adi Caspi, Jasmine A. Alvarez, Adam E. Snook, Scott A. Waldman. Oncogenic WNT/β-catenin signaling reduces MAPK signaling to suppress broad gene expression and promote colorectal cancer progression abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr LB283.
Evans et al. (Fri,) studied this question.