德国科隆大学Marce Schmiell研究团队揭示了神经元之间的功能性突触与小细胞肺癌。2025年9月10日出版的《自然》发表了这项成果。

小组发现SCLC细胞可以形成功能性突触并接受突触传递。通过结合跨物种基因组学和转录组学验证的体内插入诱变筛选，研究团队确定了motheme和人类SCLC中的神经元、突触和谷氨酸能信号传导基因集。进一步的实验揭示了SCLC细胞在体内和体外与神经元形成突触结构的能力。电生理和光遗传学实验证实癌细胞可以接受NMDA受体和GABAA受体介导的突触输入。与神经元- SCLC相互作用的潜在致癌作用相吻合，该团队发现SCLC细胞与迷走神经感觉神经元或皮质神经元共培养时具有增殖优势。

此外，抑制谷氨酸信号传导在SCLC的自体受体模型中具有治疗效果。因此，在恶性转化后，SCLC细胞似乎劫持突触信号以促进肿瘤生长，从而为治疗干预提供了新的途径。

据悉，小细胞肺癌（Small cell lung cancer， SCLC）是一种侵袭性很强的肺癌类型，具有增殖快、早期转移扩散、早期复发频繁、死亡率高的特点。最近的证据表明，神经支配在几种癌症的发生和发展中起着重要作用。肿瘤-神经元突触在胶质瘤中有报道，但周围肿瘤是否能形成这样的结构尚不清楚。

附：英文原文

Title: Functional synapses between neurons and small cell lung cancer

Author: Sakthivelu, Vignesh, Schmitt, Anna, Odenthal, Franka, Ndoci, Kristiano, Touet, Marian, Shaib, Ali H., Chihab, Abdulla, Wani, Gulzar A., Nieper, Pascal, Hartmann, Griffin G., Pintelon, Isabel, Kisis, Ilmars, Boecker, Maike, Eckert, Naja M., Ianicelli Caiaffa, Manoela, Ibruli, Olta, Weber, Julia, Maresch, Roman, Bebber, Christina M., Chitsaz, Ali, Ltz, Anna, Kim Alves Carpinteiro, Mira, Morris, Kaylee M., Franchino, Camilla A., Benz, Jonas, Prez-Revuelta, Laura, Soriano-Campos, Jorge A., Huetzen, Maxim A., Goergens, Jonas, Jevtic, Milica, Jahn-Kelleter, Hannah M., Zempel, Hans, Placzek, Aleksandra, Hennrich, Alexandru A., Conzelmann, Karl-Klaus, Tumbrink, Hannah L., Hunold, Pascal, Isensee, Joerg, Werr, Lisa, Gaedke, Felix, Schauss, Astrid, Minre, Marielle, Mller, Marie, Fenselau, Henning, Liu, Yin, Heimsoeth, Alena, Glcler Balta, Glce S., Walczak, Henning, Frezza, Christian, Jachimowicz, Ron D., George, Julie, Schmiel, Marcel

Issue&Volume: 2025-09-10

Abstract: Small cell lung cancer (SCLC) is a highly aggressive type of lung cancer, characterized by rapid proliferation, early metastatic spread, frequent early relapse and a high mortality rate1,2,3. Recent evidence has suggested that innervation has an important role in the development and progression of several types of cancer4,5. Cancer-to-neuron synapses have been reported in gliomas6,7, but whether peripheral tumours can form such structures is unknown. Here we show that SCLC cells can form functional synapses and receive synaptic transmission. Using in vivo insertional mutagenesis screening in conjunction with cross-species genomic and transcriptomic validation, we identified neuronal, synaptic and glutamatergic signalling gene sets in mouse and human SCLC. Further experiments revealed the ability of SCLC cells to form synaptic structures with neurons in vitro and in vivo. Electrophysiology and optogenetic experiments confirmed that cancer cells can receive NMDA receptor- and GABAA receptor-mediated synaptic inputs. Fitting with a potential oncogenic role of neuron–SCLC interactions, we showed that SCLC cells derive a proliferation advantage when co-cultured with vagal sensory or cortical neurons. Moreover, inhibition of glutamate signalling had therapeutic efficacy in an autochthonous mouse model of SCLC. Therefore, following malignant transformation, SCLC cells seem to hijack synaptic signalling to promote tumour growth, thereby exposing a new route for therapeutic intervention.

DOI: 10.1038/s41586-025-09434-9

Source: https://www.nature.com/articles/s41586-025-09434-9