Neural function of Netrin-1 in precancerous lesions of the pancreas
Abstract The nervous system undergoes dynamic structural remodeling to infiltrate cancerous tumors, contributing to their growth and progression. Emerging evidence indicates that neuroplasticity initiates early, with nerve terminals detecting and responding to tissue changes even during precancerous...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62299-4 |
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| author | Hiba Haidar Anaïs Bellon Karen Sleiman Mélanie Hocine Nicolas Rama Nicolas Gadot Darren R. Carpizo Patrick Mehlen Fanny Mann |
| author_facet | Hiba Haidar Anaïs Bellon Karen Sleiman Mélanie Hocine Nicolas Rama Nicolas Gadot Darren R. Carpizo Patrick Mehlen Fanny Mann |
| author_sort | Hiba Haidar |
| collection | DOAJ |
| description | Abstract The nervous system undergoes dynamic structural remodeling to infiltrate cancerous tumors, contributing to their growth and progression. 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 insights into early cancer progression. |
| format | Article |
| id | doaj-art-a1ccee30f09547e0832948b1f22bac49 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-a1ccee30f09547e0832948b1f22bac492025-08-20T03:05:10ZengNature PortfolioNature Communications2041-17232025-08-0116111310.1038/s41467-025-62299-4Neural function of Netrin-1 in precancerous lesions of the pancreasHiba Haidar0Anaïs Bellon1Karen Sleiman2Mélanie Hocine3Nicolas Rama4Nicolas Gadot5Darren R. Carpizo6Patrick Mehlen7Fanny Mann8Aix-Marseille University, CNRS, IBDMAix-Marseille University, CNRS, IBDMAix-Marseille University, CNRS, IBDMAix-Marseille University, CNRS, IBDMApoptosis, Cancer and Development Laboratory - Equipe labellisée “La Ligue,” LabEx DEVweCAN, Institut Convergence PLAsCAN, Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM U1052-CNRS UMR5286, Université de Lyon, Université Claude Bernard Lyon 1, Centre Léon BérardResearch Pathology Platform East, CRCL, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon1Department of Surgery, Division of Surgical Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA; Wilmot Cancer Center, University of RochesterApoptosis, Cancer and Development Laboratory - Equipe labellisée “La Ligue,” LabEx DEVweCAN, Institut Convergence PLAsCAN, Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM U1052-CNRS UMR5286, Université de Lyon, Université Claude Bernard Lyon 1, Centre Léon BérardAix-Marseille University, CNRS, IBDMAbstract The nervous system undergoes dynamic structural remodeling to infiltrate cancerous tumors, contributing to their growth and progression. 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 insights into early cancer progression.https://doi.org/10.1038/s41467-025-62299-4 |
| spellingShingle | Hiba Haidar Anaïs Bellon Karen Sleiman Mélanie Hocine Nicolas Rama Nicolas Gadot Darren R. Carpizo Patrick Mehlen Fanny Mann Neural function of Netrin-1 in precancerous lesions of the pancreas Nature Communications |
| title | Neural function of Netrin-1 in precancerous lesions of the pancreas |
| title_full | Neural function of Netrin-1 in precancerous lesions of the pancreas |
| title_fullStr | Neural function of Netrin-1 in precancerous lesions of the pancreas |
| title_full_unstemmed | Neural function of Netrin-1 in precancerous lesions of the pancreas |
| title_short | Neural function of Netrin-1 in precancerous lesions of the pancreas |
| title_sort | neural function of netrin 1 in precancerous lesions of the pancreas |
| url | https://doi.org/10.1038/s41467-025-62299-4 |
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