Differences in collagen structure and organization in primary and metastatic pancreatic cancer and the effects of FOLFIRINOX treatment

• Fundamental aspects of collagen structure (width, length, straightness, alignment, and density) differ between normal liver and pancreas. Normal pancreas collagen showed higher values for width, length and density, and lower values for straightness, alignment, as compared to normal liver. • Tumors that arise in the pancreas show structural features that are similar to noncancerous pancreas, suggesting that an organotypic program dictates fundamental aspects of collagen structure in primary pancreatic cancers • Collagen in the core of liver metastatic tumors was remodeled to show increased length, width, and density, and decreased straightness as compared to normal liver. Collagen structure near the tumor border were intermediate between tumor core and normal liver. • FOLFIRINOX treatment increased length, width, and density and decreased straightness at both primary tumors and liver metastases. • Our results highlight that issues of pancreatic tumor heterogeneity at primary and metastatic sites include variability in collagen structure. Pancreatic ductal adenocarcinoma (PDAC) is defined by a dense, collagen-rich stroma that limits therapeutic efficacy and drives metastasis. While collagen reorganization has been studied in resected PDAC tumors, its structure and organization in metastatic PDAC and response to chemotherapy remains poorly characterized. We evaluated collagen structure by Second Harmonic Generation (SHG) imaging of formalin fixed paraffin embedded tissue from pancreatic tumors and liver metastases of 20 PDAC patients that were untreated or treated with FOLFOX or FOLFIRINOX (FOL). Collagen fiber width, length, alignment, and density were assessed at tumor cores, tumor boundaries, and in the adjacent tissue. We document for the first time fundamental differences in these collagen structure features between normal pancreas and normal liver. Surprisingly, the structure of collagen in primary pancreatic cancer was similar to normal pancreas. Liver metastases showed alterations in collagen structure, revealing a transition from a liver-like collagen phenotype (thinner, shorter less dense collagen fibers) at the tumor border to a tumor-core phenotype with thicker, longer, less aligned, and denser collagen fibers. FOL treatment increased length, width, and density at both primary tumors and liver metastases. Overall, these findings reveal organ specific collagen remodeling in PDAC and suggest that chemotherapy with FOL modulates extracellular matrix (ECM) remodeling. These findings expand the scope of PDAC collagen structural characterization and highlight the complexity of matrix targeting strategies in metastatic disease.