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.