1717P Biomarker potential of collagens linked to fibroblast subtypes in pancreatic ductal adenocarcinoma (PDAC)

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense stroma primarily consisting of collagens. However, the biomarker potential of the collagen family and its cellular origin remains underexplored in PDAC. Recently, different cancer associated fibroblast (CAF) subtypes, such as myCAFs and iCAFs, have been implicated in PDAC progression and are the target of novel therapies. In this study, we set out to profile collagen expression in CAF subtypes and evaluate their biomarker potential in PDAC. Collagen gene expression was evaluated in a single-cell RNA-sequencing dataset (GSA: CRA001160) of 24 PDAC samples and 11 samples of pancreatic cysts, bile duct- or duodenal-tumors. Overall survival (OS) as a function of collagen gene expression was evaluated in a bulk RNA-sequencing dataset of 178 PDAC and 165 healthy pancreas samples from the TCGA and GTEx projects using univariate cox proportional hazard models. ELISAs measuring processing events of collagens were measured in serum samples of 20 patients with PDAC and compared to 33 healthy controls. Pancreatic stellate cells and fibroblasts were the primary sources of collagens. In fibroblasts, COL8A1, COL10A1, COL11A1 and COL12A1 were elevated 2.8 to 5.6-fold in PDAC compared to control samples. COL8A1 was primarily expressed in myCAFs and IL-6 positive iCAFs whereas COL10A1, COL11A1 and COL12A1 were primarily expressed in myCAFs. In TCGA and GTEx samples, COL8A1, COL10A1, COL11A1, COL12A1 were elevated in PDAC compared to healthy pancreas. High COL8A1, COL10A1, COL11A1 and COL12A1 levels were significantly associated with poor OS (HR 1.40, 1.48, 1.41, 1.39, respectively). Lastly, when measured in serum, type VIII and type XI collagens were significantly elevated in PDAC compared to healthy controls. In contrast, type X collagen was downregulated, and type XII showed no difference. Type VIII, type X, type XI and type XII collagens are associated with a subset of PDAC CAFs and are prognostic for OS. We demonstrate novel ELISAs that measure these collagens non-invasively in a liquid biopsy This may be a valuable biomarker tool for patients with PDAC and may teach important lessons about CAFs and the collagens they produce.