Nigri, Jérémy, Lan, Wenjun, Fung, Melanie L, Kayser, Charlotte, Deschênes, Astrid, Hinds, Juliene, Kaushalya, Sanjeev, Pawlak, Sara A, Thalappillil, Jennifer S, Nadella, Sandeep, Hilmi, Marc, Park, Wungki, Kappagantula, Rajya, Park, Youngkyu, Zhao, Zhen, Preall, Jonathan, Iacobuzio-Donahue, Christine A, Tracey, Kevin J, Borniger, Jeremy C, Tuveson, David A (February 2026) Myofibroblasts induce neuroplasticity to promote pancreatic inflammation and cancer progression. Cancer Discovery. ISSN 2159-8274 (Public Dataset)
Abstract
Pancreatic ductal adenocarcinoma (PDAC) co-opts the peripheral nervous system through nerve hypertrophy, axonogenesis and perineural invasion, and these processes correlate with patient morbidity and mortality. Prior work has shown that autonomic nerves directly modulate neoplastic cells in PDAC, but whether cancer-associated fibroblasts (CAFs) participate in neural remodeling is unknown. Using thick tissue sections, we identified dense neo-innervation near myofibroblastic CAFs (myCAFs) in preinvasive Pancreatic Intraepithelial Neoplasms (PanINs). Mechanistically, TGF-β produced during inflammation and neoplasia triggers myofibroblast formation, and myCAFs produce axon guidance molecules that recruit sympathetic nerves. Norepinephrine released by sympathetic nerves activates myofibroblast cultures in vitro, and sympathetic nerve depletion impairs stromal activation and PDAC growth in vivo. A chemogenetic model confirmed that fibroblast-specific α1-adrenergic signaling exacerbated pancreatic inflammation and neoplasia. Therefore, beyond direct epithelial effects, sympathetic nerves promote pancreatitis and PDAC by co-opting myofibroblasts and myCAFs as disease amplifiers, highlighting CAF subtype-specific stromal interactions as putative therapeutic targets.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders > cancer diseases & disorders diseases & disorders > cancer > cancer types > pancreatic cancer diseases & disorders > cancer > cancer types |
| CSHL Authors: | |
| Communities: | CSHL labs > Albeanu lab CSHL labs > Borniger lab CSHL labs > Preall lab CSHL labs > Spector lab CSHL labs > Tuveson lab CSHL Cancer Center Program CSHL Cancer Center Program > Cancer Genetics and Genomics Program CSHL Cancer Center Program > Cellular Communication in Cancer Program CSHL Post Doctoral Fellows CSHL labs > Zhao lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 9 February 2026 |
| Date Deposited: | 12 Feb 2026 14:17 |
| Last Modified: | 12 Feb 2026 14:17 |
| Related URLs: | |
| Dataset ID: | |
| URI: | https://repository.cshl.edu/id/eprint/42081 |
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