Abstract B009: Fibulin-3 drives tumor progression and microenvironment remodeling in CA19-9-induced pancreatic ductal adenocarcinoma

Abstract Glycosylation is a complex post-translational modification essential for development, growth, and survival. Altered glycosylation is a hallmark of cancer, yet the roles of many glycoproteins remain unclear, hampering translation of glycoprotein-related vulnerabilities into therapeutic strategies. Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal malignancies, with a five-year survival rate under 13%. For decades, serum levels of CA19-9, a terminal tetra-saccharide glycan, conjugating many secreted and cell surface proteins, has been the single-most effective biomarker to track PDA progression in patients. Recent studies have identified Fibulin-3 (Fbln3) as a secreted, CA19-9–modified matricellular glycoprotein that drives EGFR hyperactivation in the pancreatic epithelium, which is essential for PDA development. However, the functional role of Fbln3 in PDA has remained largely unexplored. Here, we show that Fbln3 promotes PDA progression and tumor microenvironment (TME) remodeling. Fbln3 expression is significantly upregulated in both human and mouse PDA tissues. Overexpression and knockdown of Fbln3 modulate PDA growth rates both in vitro and in vivo. In CA19-9–expressing KRASG12D mutant PDA organoids, Fbln3 enhances activation of key oncogenic pathways, including EGFR, NFκB, and TGFβ signaling. Notably, Fbln3 regulates the expression of IL1A and TGF, cytokines known to impact both autocrine and paracrine signaling. In syngeneic orthotopic tumor models, Fbln3 promotes the expansion of antigen-presenting cancer associated fibroblasts and reduces infiltration of CD8+ T cells, contributing to an immunosuppressive microenvironment. Taken together, these findings demonstrate that CA19-9-modified Fbln3 drives pancreatic tumor progression and TME remodeling by regulating IL1A and TGFb production, highlighting the need to further investigate its potential as a therapeutic target. Citation Format: Hyemin Song, Jasper Hsu, Satoshi Ogawa, Kristina Peck, Kassidy Curtis, Chelsea Bottomely, McKenna Stamp, Dannielle D. Engle. Fibulin-3 drives tumor progression and microenvironment remodeling in CA19-9-induced pancreatic ductal adenocarcinoma [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 B009.