Non-canonical Wnt11/PCP/YAP signaling mediates epithelial-mesenchymal transition and immunosuppressive tumor microenvironment in colorectal cancer.
TL;DR
The Wnt11/PCP/YAP axis is identified as a dual driver of CRC malignant progression and immune evasion, providing a mechanistic basis for targeted therapies and immunotherapy combination strategies.
Abstract
While canonical Wnt/β-catenin signaling is well-characterized in colorectal cancer (CRC), the role of non-canonical Wnt pathways, particularly Wnt11-mediated planar cell polarity (PCP) signaling, remains poorly understood. Here, our study elucidates the functional role of the non-canonical Wnt11/PCP/Yes-associated protein (YAP) axis in CRC progression and its immunosuppressive tumor microenvironment (TME). Transcriptomic analysis of GEO datasets revealed significant upregulation of WNT11 in CRC tissues, correlating with advanced tumor stages and poor prognosis. Bioinformatics enrichment and immune infiltration analyses implicated the Wnt11/PCP/YAP axis in promoting epithelial-mesenchymal transition (EMT), cell migration, and M2 macrophage polarization. Mechanistically, Wnt11 activated RhoA/ROCK signaling to reorganize the actin cytoskeleton, driving YAP nuclear translocation and transcriptional activation of pro-proliferative and EMT-related genes. In vitro experiments demonstrated that WNT11 knockdown or ROCK inhibition suppressed CRC cell migration and invasion, reversed EMT (via upregulated E-cadherin and downregulated N-cadherin), and polarized M2 macrophages toward an M1 pro-inflammatory phenotype. In vivo subcutaneous xenograft models confirmed that WNT11 knockdown or ROCK inhibitor treatment significantly reduced tumor growth, decreased M2 macrophage infiltration, and increased tumor apoptosis while inhibiting YAP nuclear localization and Ki-67+ proliferation. Mechanistically, Wnt11 directly interacts with FZD7 to activate PCP/ROCK signaling, which regulates YAP phosphorylation and transcriptional activity in a Hippo-independent manner, leading to CTGF upregulation. This study identifies the Wnt11/PCP/YAP axis as a dual driver of CRC malignant progression and immune evasion, providing a mechanistic basis for targeted therapies and immunotherapy combination strategies.