Abstract 359: Pancreatic cancer cachexia is associated with infiltration of immune cells into sympathetic ganglia

Abstract

Abstract The sympathetic nervous system controls the fight or flight response and regulates the physiological function of many organs. Therefore, a dysfunctional adrenergic input not only impairs normal physiology but also contributes to the ongoing pathology observed in numerous chronic conditions. This is especially true for patients suffering from cancer and cancer-associated cachexia, a multifactorial syndrome characterized by weight loss, anorexia, and increased metabolic rate. Many studies in cancer cachexia animal models demonstrated an elevated adrenergic tone, mediating white adipose tissue browning and elevating resting metabolic rate. Recent clinical studies also demonstrated signs of autonomic dysfunction in cancer cachexia patients. Indeed, treating cancer cachexia patients with beta blockers showed promising results by preventing loss of body mass, further highlighting a role for adrenergic dysfunction in driving cachexia pathophysiology. However, the mediators of adrenergic dysfunction in cancer cachexia patients remain poorly understood. To investigate this question, we used a murine model of pancreatic ductal adenocarcinoma (PDAC) associated cachexia and performed bulk RNA-sequencing of stellate ganglia (SG) (n=6) and celiac-superior mesenteric ganglia (CG-SMG) (n=6). The SG provide sympathetic innervation to the heart and brown adipose tissue, which both undergo atrophy in cancer cachexia patients. The CG-SMG provide sympathetic innervation to the liver, one of the major metabolic organs that goes awry during cachexia, along with the pancreas and the tumor. By analyzing these ganglia, we aimed to determine the molecular basis for sympathetic hyperactivity in cancer cachexia. Gene ontology analysis of our RNA-seq data revealed an enrichment of pathways associated with leukocyte migration and activation as well as regulation of inflammatory pathways (p-value < 0.0001). We complemented our RNA-seq studies with immunohistochemistry experiments of SG and CG-SMG and discovered a significant recruitment of CD45+ immune cells (Sham average: 100.6, PDAC average: 599.8; p-value < 0.001). These immune cells alter the inflammatory milieu within sympathetic ganglia, thereby providing a mechanism for dysfunctional adrenergic outflow. Considering prior studies highlighted the interaction between immune cells and sympathetic outflow in models of obesity, hypertension, and heart failure, we believe our observations point to a possible mechanism for autonomic dysfunction in cancer cachexia patients. Citation Format: Parham Diba, Mason A. Norgard, Xinxia Zhu, Tetiana Korzun, Peter R. Levasseur, Daniel L. Marks. Pancreatic cancer cachexia is associated with infiltration of immune cells into sympathetic ganglia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 359.