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Prior work has shown that autonomic nerves directly modulate neoplastic cells in PDAC, but whether cancer-associated fibroblasts (CAF) participate in neural remodeling is unknown. Using thick tissue sections, we identified dense neo-innervation near myofibroblastic CAFs (myCAF) in preinvasive pancreatic intraepithelial neoplasms. Mechanistically, TGF\u03b2 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 \u03b11-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\u2013specific stromal interactions as putative therapeutic targets.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>Pathology-associated myofibroblasts orchestrate bidirectional cross-talk with sympathetic neurons, secreting axon guidance molecules to promote nerve infiltration in inflamed and neoplastic pancreatic tissues. Specifically, \u03b11-adrenoreceptor activation in fibroblasts acts as a molecular switch that amplifies pancreatitis severity and accelerates tumor growth, revealing new paracrine and juxtacrine interactions for further therapeutic development.<\/jats:p>\n                    <jats:p>See related commentary by Hondermarck et al., p.834<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-25-1337","type":"journal-article","created":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T15:01:56Z","timestamp":1770649316000},"page":"1014-1034","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Myofibroblasts Induce Neuroplasticity to Promote Pancreatic Inflammation and Cancer 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