Extracellular Matrix Mechanobiology in Pancreatic Ductal Adenocarcinoma: Correlating In Vivo Patient Magnetic Resonance Elastography with Ex Vivo Tissue Mechanics and Histopathology

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense desmoplastic extracellular matrix (ECM) that contributes to tumor progression, therapeutic resistance, and poor patient survival. However, the relationship between in vivo imaging-derived mechanical properties, ex vivo tissue biomechanics, ECM architecture, and cellularity remains incompletely understood. Here, we combined pre-operative in vivo clinical magnetic resonance elastography (MRE) with ex vivo biomechanical testing of fresh human PDAC tissue and histopathological analyses. Nine patients undergoing pancreatic resection were prospectively enrolled. Quantitative MRE was performed pre-operatively to assess tissue stiffness through shear wave speed (c) and relative viscosity or fluidity through the loss angle ({varphi}). Fresh tumor and adjacent non-malignant tissue biopsies were subsequently analyzed ex vivo by unconfined uniaxial compression testing to determine elastic moduli and stress relaxation halftime. Histological analyses quantified collagen-rich fibrous tissue area, cell nuclei density, and nuclear morphology. Tumor tissue exhibited significantly increased stiffness and collagen fraction compared with adjacent non-malignant tissue, together with reduced cellularity, smaller nuclear area and more elongated nuclei. Ex vivo stiffness positively correlated with collagen content and negatively correlated with patient survival. Reduced stress relaxation halftime, indicative of increased tissue viscosity, was associated with lower cellularity and elongated nuclei. Importantly, pre-operative MRE parameters of the intact surrounding environment correlated significantly with ex vivo tumor mechanics, cellular organization, and survival. Specifically, a softer and less viscous surrounding environment was associated with stiffer and more viscous tumors, with lower cellularity and elongated nuclei, and poorer prognosis. These findings demonstrate that MRE-derived mechanical biomarkers reflect underlying ECM remodeling and tumor mechanobiology in PDAC. Integrating in vivo imaging with ex vivo tissue mechanics and histopathology may improve non-invasive disease characterization and support biomechanically-informed therapeutic strategies.