Deciphering the Sympathetic Nerve–Fibroblast Crosstalk in Pancreatic Cancer

Chronic stress, which dysregulates the neuroendocrine system, has long been linked to the development and progression of cancer. Sympathetic nerves, key mediators of the stress response, are increasingly recognized as active contributors to tumor initiation, progression, and metastasis, as they directly affect cancer cells and regulate the tumor microenvironment (TME). Chapter 1 of this dissertation reviews the role of sympathetic innervation across different cancer types, highlighting its impact on both immune and non-immune components of the TME. We discussed molecular mechanisms by which sympathetic signaling promotes immune evasion and drives tumor-supportive shifts in various immune populations. We also highlighted the expression and regulation of neuro-associated genes and axon guidance cues in the non-immune TME. Chapter 2 investigates the crosstalk between sympathetic nerves and cancer-associated fibroblasts (CAFs). Our research is focused on pancreatic ductal adenocarcinoma (PDAC), which is influenced by its prominent stroma, mainly composed of CAFs, and is highly innervated by sympathetic nerves. Initially, we characterized sympathetic nerves in both human and murine PDAC and demonstrated that specific intratumor sympathetic-associated marker expression correlates with poor patient survival, highlighting their clinical relevance. We developed a novel murine sympathectomy model that is specific to the sympathetic nervous system, localized to the pancreas, and allows for long-term denervation. This model serves as a valuable tool for studying neural influences in cancer models. Using sympathetic nerve-CAF paracrine co-culture systems, we demonstrate that sympathetic nerves promote CAF activation and extracellular matrix remodeling, both of which are key hallmarks of a tumor-promoting stroma. We also identified several upregulated genes linked to tumor-promoting phenotypes. Conversely, CAF signaling exacerbates the nerve injury response, indicating that stromal signals might influence nerve growth and organization during tumor progression. Together, these findings reveal a dynamic and reciprocal relationship between sympathetic nerves and CAFs in PDAC, suggesting a potential targetable axis for therapy. Chapter 3 reviews the main findings and their implications, outlines key limitations, and suggests future research directions. This dissertation lays the groundwork for further investigation into the roles of distinct nerve subtypes in PDAC, broadens the utility of our sympathetic ablation model to other tumor types, and highlights candidate targets within the neuro-fibroblast axis for future therapeutic exploration.