Preprint Highlight: Collagen remodeling dictates pancreatic cancer bioenergetics and outcome through DDR1 activation or degradation.

Abstract

Aberrant desmoplasia (e.g., collagen deposition) is a prominent hallmark of pancreatic ductal adenocarcinoma (PDAC) pathogenesis. The mechanisms and signaling pathways impacted by the prevalent increase in collagen deposition are poorly understood. This study demonstrated opposing roles of fibrolytic stroma (cleaved type I collagen) and inert stroma (intact type I collagen) in driving PDAC tumorigenicity. Cleaved type I collagen activates discoidin domain receptor 1 (DDR1), leading to increased tumor growth and liver metastases, macropinocytosis, metabolism, mitochondrial biogenesis, and poor patient outcomes. These effects were inhibited by intact type I collagen. This study describes new roles of DDR1-mediated regulation of macropinocytosis and mitochondrial biogenesis, delineates stromal states as oncogenic drivers of PDAC, and advances our understanding of aberrant desmoplasia.