Abstract B040: Neural control of cancer-associated fibroblasts in PDAC

Abstract Pancreatic ductal adenocarcinoma (PDAC) poses a formidable challenge to public health, with a dismal 5-year survival rate and a projected rise as the second leading cause of cancer-related deaths by 2030. The pathogenesis of PDAC involves a robust desmoplastic reaction and a complex tumor microenvironment (TME), constituting up to 80% of the tumor volume. The TME is a heterogeneous mixture of cells, including cancer-associated fibroblasts (CAFs), immune cells, endothelial cells, and neurons, which all interact and contribute to disease progression. However, the precise interplay between the tumor-associated nerves and PDAC development remains unclear. It is known that neural remodeling within the tumor microenvironment are closely associated with intense neuropathic pain, metastasis, and shortened patient survival. The prevalence of nerve fibers present in the dense desmoplastic stroma of PDAC tumors suggest a potential interaction between neurons and stromal cells, particularly CAFs, through various paracrine signaling mechanisms, influencing CAF behavior and facilitating neural remodeling, ultimately driving PDAC progression. Our investigation revealed that the neurotransmitter noradrenaline, induces calcium signaling and prompt contraction in pancreatic stellate cells (PSCs). Preliminary in vitro findings indicate that this calcium signaling is mediated by alpha 1 adrenergic receptors. Whole-mount 3D imaging mouse PDAC tissues, indicates a spatial organization of adrenergic neurons in immediate proximity to neoplastic cells and cancer-associated fibroblasts. Moreover, our study demonstrated that noradrenaline and alpha 1 agonists modulate extracellular matrix (ECM) production and cytokine secretion in PSCs and CAFs. Finally, we discovered that chemical ablation of the sympathetic nervous system significantly suppresses tumor growth while promoting metastasis, underscoring the critical role of the noradrenergic system in tumor development. Collectively, our findings propose that noradrenergic neurons possess the capacity to influence CAF behavior, opening new avenues of investigation to unravel the intricate crosstalk between neural regulation and tumor progression in PDAC. Citation Format: Jeremy Nigri, Wenjun Lan, Sangeeta S Chavan, Youngkyu Park, Jeremy Borniger, Kevin J Tracey, David A Tuveson. Neural control of cancer-associated fibroblasts in PDAC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B040.