Obesity-mediated intratumoral innervation increases pancreatic cancer tumorigenesis

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 pro-tumorigenic type 2 immune microenvironment accelerating 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.