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A peritumoral microenvironment engaged by Reg-EXTL3 axis fosters nerve-cancer interactions in pancreatic ductal adenocarcinoma
 

A peritumoral microenvironment engaged by Reg-EXTL3 axis fosters nerve-cancer interactions in pancreatic ductal adenocarcinoma

Shan Zhang, Fang-Yuan Dong, Shuqi Cai, Bin Zhou, Luju Jiang, Li-Peng Hu, Yu-Heng Zhu, Hui Li, Xiao-Mei Yang, Zhiwei Cai, …
Neuron (Cambridge, Mass.), Vol.114(18), pp.3381-3399.e11
2026-05-07
: https://doi.org/10.1016/j.neuron.2026.03.039
: 42102806
 
cancer neuroscience neural remodeling neural invasion nerve dependence
Tumor innervation (TIN) and perineural invasion (PNI) are well-established pathological features of pancreatic ductal adenocarcinoma (PDAC) that drive its aggressiveness and associated pain. Here, we reveal that regenerating islet-derived (Reg) proteins, secreted by peritumoral exocrine acinar cells, facilitate TIN and PNI through two paracrine mechanisms. In PDAC cells, Reg proteins drive cancer invasiveness along nerves via autocrine transforming growth factor β (TGF-β) signaling. In neurons, Reg proteins are neurotrophic and potentiate neuronal excitability, resulting in hyperinnervation and pain. Interleukin-22, primarily produced by CD4+ T cells, triggers Reg expression. Exostosin-like glycosyltransferase 3 (EXTL3) is the functional receptor for Reg proteins in both cell types. Genetic silencing of Reg or EXTL3 reduces TIN, nerve-cancer proximity, PDAC progression, and pain behavior in mice. Clinically, the Reg-EXTL3-TGF-β axis correlates with increased TIN and PNI severity, poor prognosis, and greater pain. Thus, targeting the Reg-EXTL3 axis may be an attractive strategy for mitigating neural-associated adverse consequences in PDAC.
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