Abstract 2576: Crosstalk between cancer-associated fibroblasts and sympathetic nerves promotes pancreatic ductal adenocarcinoma progression

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, with a 5-year survival rate of 12.8%. This aggressive malignancy is composed of a heterogenous tumor microenvironment (TME), including cancer-associated fibroblasts (CAFs) and sympathetic neurons. The abundance of CAFs and sympathetic neurons correlates with tumor progression and is often associated with poor prognosis of PDAC patients. However, the precise role of CAF-nerve interactions in cancer progression and metastasis remains unclear. To explore our hypothesis that these bidirectional interactions can be tumor-supportive, we used advanced imaging and sequencing techniques, an in vivo tumor denervation murine model, and in vitro CAF-sympathetic neuron coculture systems. Compared to human PDAC tumors, we affirmed that sympathetic innervation is recapitulated in murine PDAC tumors, and these intratumor nerves are similarly surrounded by an abundance of CAFs. To focus on the interaction between CAFs and sympathetic nerves, we developed and optimized in vitro coculture systems. These cocultures initially revealed that CAFs consistently interact with nerve fibers and significantly increase sympathetic nerve outgrowth. Transcriptional analysis of these co-cultures further identified genes upregulated in CAFs that promote adhesion, ECM deposition, and neuroactive ligand-receptor interactions, while sympathetic nerves upregulated pathways associated with nerve injury response. To further interrogate the impact of sympathetic innervation in the PDAC TME, we specifically and locally ablated sympathetic nerves in murine orthotopic PDAC tumors and spatially evaluated the cellular and molecular changes in response. Collectively, our findings suggest that the crosstalk between sympathetic nerves and CAFs may modulate CAF behavior, enhance tumor innervation, and drive tumor-promoting phenotypes in PDAC progression. Citation Format: Ariana Sattler, Parham Diba, Tetiana Korzun, Marigold Kuykendall, Kevin MacPherson-Hawthorne, Mara Sherman, Teresa A. Zimmers, Sebnem E. Eksi. Crosstalk between cancer-associated fibroblasts and sympathetic nerves promotes pancreatic ductal adenocarcinoma progression [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 2576.