Abstract 2048: Extracellular vesicle-derived MASP2 as a prognostic indicator in pancreatic cancer

Abstract Advanced pancreatic cancer (APC) has an overall survival (OS) of 10 months with chemotherapy, yet some patients live only a few weeks whereas others up to two years. Novel early biomarkers are needed to guide prognostication and first-line chemotherapy efficacy, prior to tumor progression or treatment toxicity, which often preclude further therapy. In this study, serially collected serum extracellular vesicles (EVs) from chemotherapy-treated advanced pancreatic cancer (APC) patients were analyzed using mass spectrometry at three critical timepoints: pre-treatment, best response, and treatment resistance. Differentially expressed candidate proteins were identified, validated by ELISA, and correlated with treatment response and prognosis. Functional association studies were conducted using in-vitro assays with primary and metastatic pancreatic cancer (PC) cell lines, while immunohistochemistry (IHC) on tumor biopsies was performed for protein localization. Mass spectrometry analysis identified nine candidate proteins, with MASP2 emerging as the most promising candidate for further investigation. A >20% decline in EV-MASP2 levels after 2 months (M2) of chemotherapy predicted treatment response in 80% of responders (n=25), whereas a >20% increase predicted treatment resistance in 73% of non-responders (n=15). Analysis of a larger cohort (n=75) showed that a decrease vs increase at M2 was prognostic for EV-MASP2 (OS 11 vs. 8 months; p=0.0037) but not for CA19-9 (OS 11 vs. 12 months respectively, p=0.70). In situations where CA19-9 is not evaluable, EV-MASP2 retained prognostic significance. In-vitro studies indicate that systemic changes in EV-MASP2 levels are not directly driven by primary or metastatic PC cells, consistent with IHC staining patterns showing minimal or no MASP2 expression in tumor cells and moderate expression in stromal regions of both primary tumors and liver metastatic sites. In conclusion, our work indicates that serial analysis of serum EV proteins is a promising approach to identifying novel biomarkers for treatment response and prognosis in APC. Findings from this study suggest that changes in circulating EV-MASP2 levels soon after chemotherapy initiation may help guide treatment decisions and improve patient outcomes. Citation Format: Shatovisha Dey, Deep Pandya, Tammy Lo, Ryan Narbutas, Bhavna Khandpur, Pramila Krumholtz, Mohammadreza Shervinrad, Kiyoe Sullivan, Deborah August, Sarah Evans, Saraswathi Nair, Nader Okby, Gregory Niland, Richard C. Frank. Extracellular vesicle-derived MASP2 as a prognostic indicator in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2048.