YAP1-driven tumor-like cancer-associated fibroblasts modulate biomechanics of pancreatic ductal adenocarcinoma.

Abstract

BACKGROUND: In pancreatic ductal adenocarcinoma (PDAC), activation of Yes-associated protein 1 (YAP1) is linked to increased extracellular matrix (ECM) stiffness, yet how YAP1 interacts with cancer-associated fibroblasts (CAFs) and their subtypes to promote stromal remodeling remains unclear. METHODS: Utilizing single-cell RNA sequencing (scRNA-seq) data to identify CAF subsets; validating the role of a specific subset, tumor-like CAFs (tCAFs), in YAP1-dependent promotion of ECM stiffness, epithelial-mesenchymal transition (EMT) combining the YAP1 inhibitor verteporfin with gemcitabine in KPC mouse models to assess effects on tCAF function, stromal stiffness, and survival; and employing magnetic resonance elastography (MRE) to quantify tumor stiffness in PDAC patients and mouse models. RESULTS: scRNA-seq identified a novel CAF subset (tCAFs) enriched in tumors with high YAP1 activity; tCAFs and mCAFs can mutually differentiate, and this process is regulated by YAP1 activity; in KPC mice, the combination of verteporfin and gemcitabine suppressed tCAF function, reduced stromal stiffness, and improved survival; MRE can accurately quantify tumor stiffness in PDAC patients; elevated YAP1 activity induces a stiffer, more highly cross-linked ECM, which is associated with increased tumor aggressiveness and shortened survival. CONCLUSIONS: YAP1 and tumor-like CAFs (tCAFs) play a pivotal role in driving desmoplasia in PDAC. YAP1 mediates the conversion of mCAFs to tCAFs and remodels the extracellular matrix (ECM), while high YAP1 activity in tCAFs regulates EMT induction to propel disease progression. Targeting the YAP1-tCAF axis can suppress desmoplasia and improve therapeutic outcomes. Magnetic resonance elastography (MRE) holds significant potential for non-invasive monitoring of stromal mechanics, offering a new perspective for stromal therapies in PDAC.