Abstract 1341: Non-invasive biomarkers quantifying collagens essential for embryogenesis are elevated in the circulation of solid tumor patients and may guide drug development

Abstract

Abstract Background Collagen remodeling is an essential part of embryogenesis and defines tissue structure and function in adulthood. The 28 different collagens are all important for maintaining tissue homeostasis and are deregulated in cancer. The abundant, major collagens, such as type I collagen, serve a structural role, whereas the less abundant, minor collagens serve a more regulatory role. Fibroblasts are the primary source of collagens and different cancer-associated fibroblast (CAF) subtypes, such as myCAFs or iCAFs, have been attributed important roles in cancer and are the target of novel therapies. Emerging evidence suggests minor collagens may be aberrantly expressed in cancer and linked to specific fibroblast subtypes, suggesting novel biomarker potential. This study aimed to evaluate the association between different CAF subtypes and collagen expression. Methods We investigated collagen expression in pancreatic cells and CAF subtypes in a publicly available single-cell RNA-Seq dataset (GSA: CRA001160). 24 samples were from patients with pancreatic ductal adenocarcinoma (PDAC) as this is one of the most collagen rich tumor types, and 11 samples were from pancreatic cysts, bile duct- or duodenal-tumors. In addition, we generated a collagen turnover profile using a panel of immunoassays to measure specific collagen fragments in the serum of 220 patients with various solid tumor types and 33 healthy controls. The included immunoassays measured collagen epitopes associated with either formation, degradation, or other modifications of collagens. Results Based on the single-cell RNA-Seq dataset, fibroblasts were the primary source of collagens. Major collagens, including COL1A1, COL3A1, COL4A1, and COL6A1, were highly expressed in both healthy fibroblasts and PDAC CAFs, whereas minor collagens such as COL8A1, COL10A1, COL11A1, and COL12A1 were exclusively expressed in CAFs. When further examining the CAF subtypes, major collagens were expressed in all CAF subtypes, with high expression in myCAFs and iCAFs. In contrast, the minor collagens were exclusively expressed in the myCAFs. When measuring these collagens in serum, the minor collagens were elevated across all cancer types when compared to healthy control serum. Contrastingly, the major collagens were not elevated in any cancers or only elevated in a few cancer types. Conclusions Collagens in general are highly expressed in cancer. However, minor collagens may be more cancer-specific than major collagens. Our findings also suggest that minor collagens may be specific to certain subtypes of CAFs. These collagens can be quantified in blood, making them promising actionable biomarkers that may guide drug development aimed at targeting CAFs. Citation Format: Jeppe Thorlacius-Ussing, Christina Jensen, Emilie Madsen, Morten Karsdal, Nicholas Willumsen. Non-invasive biomarkers quantifying collagens essential for embryogenesis are elevated in the circulation of solid tumor patients and may guide drug development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1341.