Zhi Xiaofei, Wu Feijing, Qian Jin, Ochiai Yosuke, Lian Guodong, Malagola Ermanno, Zheng Biyun, Tu Ruhong, Zeng Yi, Kobayashi Hiroki, Xia Zhangchuan, Wang Ruizhi, Peng Yueqing, Shi Qiongyu, Chen Duan, Ryeom Sandra W, Wang Timothy C
Division of Digestive and Liver Diseases, Irving Cancer Research Center, Columbia University Medical Center, New York, NY, USA.
Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, China.
Nature. 2025 Apr;640(8059):802-810. doi: 10.1038/s41586-025-08591-1. Epub 2025 Feb 19.
Cancer cells have been shown to exploit neurons to modulate their survival and growth, including through the establishment of neural circuits within the central nervous system. Here we report a distinct pattern of cancer-nerve interactions between the peripheral nervous system and gastric cancer. In multiple mouse models of gastric cancer, nociceptive nerves demonstrated the greatest degree of nerve expansion in an NGF-dependent manner. Neural tracing identified CGRP peptidergic neurons as the primary gastric sensory neurons. Three-dimensional co-culture models showed that sensory neurons directly connect with gastric cancer spheroids. Chemogenetic activation of sensory neurons induced the release of calcium into the cytoplasm of cancer cells, promoting tumour growth and metastasis. Pharmacological ablation of sensory neurons or treatment with CGRP inhibitors suppressed tumour growth and extended survival. Depolarization of gastric tumour membranes through in vivo optogenetic activation led to enhanced calcium flux in jugular nucleus complex and CGRP release, defining a cancer cell-peptidergic neuronal circuit. Together, these findings establish the functional connectivity between cancer and sensory neurons, identifying this pathway as a potential therapeutic target.
癌细胞已被证明会利用神经元来调节其存活和生长，包括通过在中枢神经系统内建立神经回路来实现。在此，我们报告了外周神经系统与胃癌之间一种独特的癌 - 神经相互作用模式。在多种胃癌小鼠模型中，伤害性神经以依赖神经生长因子（NGF）的方式表现出最大程度的神经扩张。神经追踪确定降钙素基因相关肽（CGRP）肽能神经元为主要的胃感觉神经元。三维共培养模型显示感觉神经元直接与胃癌球体相连。感觉神经元的化学遗传激活诱导癌细胞胞质内钙的释放，促进肿瘤生长和转移。感觉神经元的药理学消融或用CGRP抑制剂治疗可抑制肿瘤生长并延长生存期。通过体内光遗传学激活使胃肿瘤膜去极化导致颈核复合体中钙通量增加和CGRP释放，确定了一种癌细胞 - 肽能神经元回路。总之，这些发现确立了癌症与感觉神经元之间的功能连接，将该途径确定为一个潜在的治疗靶点。
