Obesity-Linked Pancreatic Fat Rewires Tumor Nerves to Promote Cancer Growth

Abstract

Obesity, affecting 74% of U.S. adults, is strongly linked to pancreatic steatosis and a 60% increased risk of pancreatic ductal adenocarcinoma (PDAC), with double the mortality rate, yet its mechanisms of aggressiveness remain unclear. Studies show obesity-driven PDAC has a type 2 immune-dominated tumor-immune microenvironment (TIME), characterized by immune-suppressive myeloid cells that suppress CD8$^+$ T cells and promote tumor progression. To unravel these mechanisms, we use GEMMs, pharmacological inhibitors, transcriptomic analyses (RNA-seq, spatial transcriptomics, scRNA-seq), and advanced imaging (3D iDISCO, confocal microscopy). Our mechanistic study, employing the tools mentioned, reveals that obesity-driven PDAC exhibits significantly higher nerve innervation and adipocyte infiltration, which promotes tumor progression. This increased neuronal innervation in obese PDAC tumors is mediated by neurotrophic factors NGF and NrCAM, released by pancreatic adipocytes within the tumor bed. We found that neurotransmitter release regulates cytokine and chemokine expression, causing dramatic remodeling of the tumor-immune microenvironment (TIME). Specifically, obesity-driven innervation-mediated neuro-adrenergic signaling activates the $\beta_2$-adrenergic receptor ($\beta_2$-AR) on PDAC cells, enhancing the production and secretion of alarmins like IL-33 and chemokines. Importantly, mitigating adrenergic signaling through (i) pharmacological $\beta_2$-AR antagonists ($\beta$-blockers), (ii) chemical denervation with 6-OHDA, or (iii) a thermoneutral model, reduced obesity-mediated tumorigenesis. These findings suggest that reducing neuro-adrenergic signaling promotes a pro-inflammatory TIME and significantly curtails obesity-driven PDAC tumorigenesis.