CAF-derived TGF-β1 activates an LBH-mediated β-catenin stabilization program to drive gastric cancer progression
TL;DR
It is shown that the transcriptional cofactor LBH drives mutation-independent Wnt activation and malignant progression in GC via a tumour microenvironment-regulated post-translational stabilization mechanism, elucidate a critical tumour–stroma crosstalk mechanism and establish the targeted disruption of the LBH–β-catenin interaction interface as a clinically relevant therapeutic strategy for advanced gastric cancer.
Abstract
Aberrant Wnt/β-catenin signaling is frequently observed in gastric cancer (GC); however, the mechanisms sustaining this pathway in the absence of canonical genetic mutations remain incompletely understood. Here we show that the transcriptional cofactor LBH drives mutation-independent Wnt activation and malignant progression in GC via a tumour microenvironment-regulated post-translational stabilization mechanism. By integrating single-cell transcriptomics with multicentre clinical cohorts, we identify LBH as a principal regulator of epithelial–mesenchymal transition and peritoneal metastasis, and its elevated expression independently predicts poor patient survival. Mechanistically, fi broblast activation protein (FAP)-positive cancer-associated fi broblasts (CAFs) secrete TGF-β1, which selectively induces LBH expression in adjacent GC cells via the SMAD2/3 signaling cascade. Crucially, LBH physically interacts with β-catenin, providing steric hindrance that prevents destruction complex-mediated phosphorylation and subsequent ubiquitin-proteasomal degradation. This FAP⁺ CAF–TGF-β1–LBH–β-catenin paracrine axis continuously sustains global Wnt transcriptional output without requiring intrinsic genetic mutations. Our findings elucidate a critical tumour–stroma crosstalk mechanism and establish the targeted disruption of the LBH–β-catenin interaction interface as a clinically relevant therapeutic strategy for advanced gastric cancer.