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Emerging evidence indicates that neuroplasticity initiates early, with nerve terminals detecting and responding to tissue changes even during precancerous stages. Notably, dense sympathetic axon sprouting has been observed around pancreatic intraepithelial neoplasia (PanIN), a common precursor lesion to pancreatic cancer. However, the molecular signals driving this early neuroplasticity and its functional consequences remain poorly understood. Here, we identify the axon guidance molecule Netrin-1 as a key factor secreted by pancreatic cells within precursor lesions of pancreatic cancer. Netrin-1 promotes sympathetic axon growth and branching through its receptor, Deleted in Colorectal Cancer (DCC). Inhibition of Netrin-1 disrupts sympathetic axon remodeling while accelerating PanIN formation and progression, driven by increased precancerous cell proliferation. Furthermore, human pancreatic tissue analysis corroborates Netrin-1 expression in precursor lesions. These findings suggest that Netrin-1-driven sympathetic neuroplasticity plays a protective role in the precancerous microenvironment by modulating local cellular dynamics, providing new insights into early cancer progression.<\/jats:p>","DOI":"10.1101\/2025.05.14.654046","type":"posted-content","created":{"date-parts":[[2025,5,19]],"date-time":"2025-05-19T01:50:14Z","timestamp":1747619414000},"source":"Crossref","is-referenced-by-count":0,"title":["Neural function of Netrin-1 in precancerous lesions of the pancreas"],"prefix":"10.64898","author":[{"given":"Hiba","family":"Haidar","sequence":"first","affiliation":[{"name":"Aix-Marseille University, CNRS, IBDM, Marseille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0198-8538","authenticated-orcid":false,"given":"Ana\u00efs","family":"Bellon","sequence":"additional","affiliation":[{"name":"Aix-Marseille University, CNRS, IBDM, Marseille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3249-4682","authenticated-orcid":false,"given":"Karen","family":"Sleiman","sequence":"additional","affiliation":[{"name":"Aix-Marseille University, CNRS, IBDM, Marseille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M\u00e9lanie","family":"Hocine","sequence":"additional","affiliation":[{"name":"Aix-Marseille University, CNRS, IBDM, Marseille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1614-7755","authenticated-orcid":false,"given":"Nicolas","family":"Rama","sequence":"additional","affiliation":[{"name":"Apoptosis, Cancer and Development Laboratory - Equipe labellis\u00e9e \u201cLa Ligue,\u201d LabEx DEVweCAN, Institut Convergence PLAsCAN, Centre de Recherche en Canc\u00e9rologie de Lyon (CRCL), INSERM U1052-CNRS UMR5286, Universit\u00e9 de Lyon, Universit\u00e9 Claude Bernard Lyon 1, Centre L\u00e9on B\u00e9rard, 69008 Lyon, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicolas","family":"Gadot","sequence":"additional","affiliation":[{"name":"Research Pathology Platform East, CRCL, INSERM U1052-CNRS UMR5286, Centre L\u00e9on B\u00e9rard, Universit\u00e9 de Lyon, Universit\u00e9 Claude Bernard Lyon1, Lyon, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3824-0160","authenticated-orcid":false,"given":"Darren","family":"Carpizo","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Surgical Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA; Wilmot Cancer Center, University of Rochester, Rochester, NY, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1743-5417","authenticated-orcid":false,"given":"Patrick","family":"Mehlen","sequence":"additional","affiliation":[{"name":"Apoptosis, Cancer and Development Laboratory - Equipe labellis\u00e9e \u201cLa Ligue,\u201d LabEx DEVweCAN, Institut Convergence PLAsCAN, Centre de Recherche en Canc\u00e9rologie de Lyon (CRCL), INSERM U1052-CNRS UMR5286, Universit\u00e9 de Lyon, Universit\u00e9 Claude Bernard Lyon 1, Centre L\u00e9on B\u00e9rard, 69008 Lyon, France"},{"name":"Netris Pharma, 69008 Lyon, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4839-4347","authenticated-orcid":false,"given":"Fanny","family":"Mann","sequence":"additional","affiliation":[{"name":"Aix-Marseille University, CNRS, IBDM, Marseille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026041122285267000_2025.05.14.654046v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-05968-y"},{"key":"2026041122285267000_2025.05.14.654046v1.2","first-page":"7593","article-title":"Cancer-Related Axonogenesis and Neurogenesis in Prostate Cancer","volume":"14","year":"2009","journal-title":"Clin Cancer Res"},{"key":"2026041122285267000_2025.05.14.654046v1.3","doi-asserted-by":"crossref","unstructured":"Magnon, C. et al. 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