Abstract B023: Fibulin-3 promotes tumor progression and microenvironment remodeling in CA19-9-expressing pancreatic ductal adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies, with a five-year survival rate below 13%. Although carbohydrate antigen 19-9 (CA19-9) is widely used as a prognostic biomarker for PDA, the functional roles of CA19-9-modified proteins in driving tumor progression remain poorly understood. Fibulin-3 (Fbln3), an extracellular matrix glycoprotein, is upregulated in advanced PDAC and has been identified as a CA19-9-modified protein. However, its precise molecular mechanisms in CA19-9-positive PDAC have not been elucidated. To investigate the function of Fbln3 in CA19-9-expressing PDAC, we utilized our unique CA19-9-inducible mouse and 3D organoid models. We found that Fbln3 plays as a driver of tumor growth in vivo and regulates multiple oncogenic signaling pathways, including Egfr, Nf-kb, and Smad2. Both genetic knockdown (KD) and pharmacological inhibition of Fbln3 suppressed activation of these pathways, highlighting its central role in PDAC progression. In addition, we found that Fbln3 promotes the expression of Il1a and Tgfb, cytokines critical for tumor microenvironment (TME) remodeling, particularly through induction of antigen-presenting cancer-associated fibroblasts (apCAFs). Orthotopic tumors with Fbln3 KD exhibited reduced apCAF populations, which are known to interact with Cd4+ T cells and promote their differentiation into immunosuppressive regulatory T cells. Moreover, we found a significant increase of Cd8+ T cell infiltration in Fbln3 KD tumors, suggesting a shift toward a less immunosuppressive TME. Notably, Fbln3 KD did not affect tumor growth in immunodeficient mice, supporting an immune-dependent mechanism of tumor progression. Altogether, our findings demonstrate that Fbln3 mediates tumor progression and immunosuppressive TME remodeling in CA19-9-positive PDAC through regulation of IL1A and TGFB across multiple oncogenic pathways. These results highlight Fbln3 as a promising therapeutic target for improving outcomes in PDAC.