Pancreatic Cancer Progression Involves Increased Lysyl Oxidase-Mediated Collagen Cross-Links as Part of the Desmoplastic Reaction

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and lethal disease characterized by extensive extracellular matrix (ECM) remodeling and fibrosis. In general, the formation of a desmoplastic stroma is associated with dynamic ECM remodeling and resistance to most standard-of-care treatments, such as conventional chemotherapy. Here, we report on alterations to core ECM and ECM remodeling enzymes, which include significant changes in levels of lysyl hydroxylase and oxidase enzymes that modulate collagen cross-linking reactions. Amino acid analysis and a novel cross-linking proteomics approach were employed to further explore these structural changes, revealing significantly elevated levels of collagen cross-linked products and several type I collagen cross-linked N-terminal telopeptides (NTX). Our findings suggest that these modifications not only enhance tumor stiffness and facilitate cancer cell invasion but also present potential biomarkers for early PDAC detection. This research contributes to the evolving landscape of PDAC treatment strategies, proposing new avenues for therapeutic intervention targeting ECM remodeling.