Haidar Hiba, Bellon Anaïs, Sleiman Karen, Hocine Mélanie, Rama Nicolas, Gadot Nicolas, Carpizo Darren R, Mehlen Patrick, Mann Fanny
Aix-Marseille University, CNRS, IBDM, Marseille, France.
Apoptosis, 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 Bérard, Lyon, France.
Nat Commun. 2025 Aug 2;16(1):7094. doi: 10.1038/s41467-025-62299-4.
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.
神经系统会经历动态的结构重塑以浸润癌性肿瘤，促进肿瘤的生长和进展。新出现的证据表明，神经可塑性在早期就已启动，即使在癌前阶段，神经末梢也能检测并响应组织变化。值得注意的是，在胰腺癌常见的前体病变——胰腺上皮内瘤变（PanIN）周围观察到了密集的交感神经轴突发芽。然而，驱动这种早期神经可塑性的分子信号及其功能后果仍知之甚少。在此，我们确定轴突导向分子Netrin-1是胰腺癌前体病变中胰腺细胞分泌的关键因子。Netrin-1通过其受体——结直肠癌缺失基因（DCC）促进交感神经轴突的生长和分支。抑制Netrin-1会破坏交感神经轴突重塑，同时加速PanIN的形成和进展，这是由癌前细胞增殖增加所驱动的。此外，对人类胰腺组织的分析证实了Netrin-1在前体病变中的表达。这些发现表明，Netrin-1驱动的交感神经可塑性通过调节局部细胞动态，在癌前微环境中发挥保护作用，为早期癌症进展提供了见解。
