Obesity-Mediated Intratumoral Innervation Increases Pancreatic Cancer Tumorigenesis

Abstract

The incidence of pancreatic ductal adenocarcinoma (PDAC) is on the rise and host factors like obesity increase risk by 60% and mortality by two-fold; however, the mechanisms that drive obesity-associated tumorigenesis are poorly understood. Here, we showed that obesity-mediated pancreatic steatosis was associated with a higher level of neo-innervation in PDAC. Neo-innervation mostly comprised sympathetic neurons that released catecholamines, which ligated the adrenergic receptor on both tumor and immune cells, subsequently, activating a downstream signaling cascade that led to a type 2 immune pro-tumorigenic microenvironment expediting tumorigenesis. Further, we identified NgCAM-related cell adhesion molecule (NrCAM) and nerve growth factor (NGF) as major mediators secreted by adipocytes that drove neurogenesis. Targeting neuro-adrenergic signaling by nerve ablation or pharmacologic approaches abolished obesity-related tumor progression. Overall, this study advances our understanding of the fundamental biology underpinning obesity-mediated neo-innervation and its causal link to exacerbating PDAC development, providing new avenues for therapeutic intervention.

Note:
Funding Information: This study was supported by 5R00CA218891-04 (P.D.); 1R01CA262822-01 (P.D.), The Roswell Park Alliance Foundation-62-2839-01 (P.D.); American Cancer Society (ACS) grant DBG-24-1309585-01-IBCD. N.D. was partially funded by CRC1324 Z02. S.A. was supported by NCI R01 CA250412.

Declaration of Interests: P.D. and S.S.M. have a patent pending on adipocyte-mediated neurogenesis.

No other conflicts declared.

Ethics Approval Statement: All animal procedures were approved by the Institutional Animal Care and Use Committee (IACUC) at Roswell Park Comprehensive Cancer Center.

Keywords: Obesity, pancreatic cancer, NGF, NrCAM, iDISCO imaging, cytokines, neurons, catecholamines, chemokines, cytokines, MDSC, macrophages