Abstract A127: Vascular heterogeneity influences treatment response in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy, in part due to its heterogeneous tumor microenvironment. Most PDAC tumors are poorly vascularized and embedded within densely fibrotic stroma; however, in prior computational analyses, we identified a subset of PDAC tumors with hyper-vascular features. In this study, we sought to determine the extent of vascular heterogeneity in PDAC and its functional consequences. Analysis of human tumor specimens revealed that approximately 10-20% of human tumors display features of hyper-vascularity. Using a panel of clonal murine cell lines that recapitulate this heterogeneity, we demonstrate that VEGFA-mediated angiogenesis does not account for the increased vessel density. Functionally, we further show that hyper-vascular tumors display enhanced sensitivity to both chemotherapy and anti-angiogenic therapy. These findings help explain the limited efficacy of VEGFA-targeted therapies in unselected PDAC cohorts and highlight vessel density as a potential biomarker for patient stratification. Citation Format: Samantha B. Kemp, William B. Sullivan, Benjamin M. Kahn, Jonathan H. Sussman, Il-Kyu Kim, Takeshi Katsuda, Sidney Mahan, Margo I. Orlen, Samuel D. Zwernik, Kailee M. Hartway, Nina G. Steele, Agnieszka K. Witkiewicz, Erik S. Knudsen, Ben Z. Stanger. Vascular heterogeneity influences treatment response in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A127.