Hippo-YAP/TAZ signaling in gastric cancer: orchestrating epithelial-stromal heterogeneity, plasticity, and therapy resistance.

Abstract

Gastric cancer is a lethal malignancy with highly variable clinical behavior, reflecting both inter-tumor diversity and marked heterogeneity within individual lesions. Large-scale genomics data (including TCGA and ACRG) has delineated recurring molecular subtypes, while expression- and immunohistochemistry-based schemes provide clinically practical surrogates. However, single-cell and spatial profiling reveal that most tumors comprise multiple malignant epithelial states alongside diverse cancer-associated fibroblast (CAF) and immune programs that vary spatially, evolve during progression, and are remodeled by therapy. The Hippo pathway effectors YAP and TAZ act as central integrators of oncogenic, inflammatory, and mechanical cues that coordinate these dynamic states. In gastric cancer, YAP/TAZ activity is enriched in diffuse/EMT-like and mesenchymal phenotypes, associates with peritoneal dissemination, and contributes to immune evasion and treatment resistance. Here, we link YAP/TAZ activity to gastric cancer subtype heterogeneity and emphasize two interconnected dimensions: (i) cell heterogeneity, encompassing coexisting epithelial lineage states and CAF subsets within tumors; and (ii) cell plasticity, highlighting reversible transitions that enable invasion, metastasis, and drug resistance. Finally, we propose a framework of YAP/TAZ-governed epithelial-stromal ecotypes and discuss implications for biomarkers and rational combination strategies incorporating Hippo-targeted agents with chemotherapy, stromal modulation, and immunotherapy.