近日，德国慕尼黑工业大学Ihsan Ekin Demir及其课题组的论文发现了感觉神经元通过谷氨酸能神经元癌伪突触驱动胰腺癌进展。相关论文于2025年9月25日发表在《癌细胞》杂志上。

该研究团队在脑外癌即胰腺导管腺癌（PDAC）中证明了感觉神经末梢和癌细胞之间存在伪突触连接。这些突触位点在癌细胞上选择性富集谷氨酸能N-甲基-D-天冬氨酸受体（NMDA）亚基NMDAR2D (GRIN2D)，使PDAC细胞对神经元源性谷氨酸产生反应，促进肿瘤生长和扩散。有趣的是，神经元通过神经元癌伪突触中的GRIN2D型谷氨酸受体将共培养的PDAC细胞亚群转化为钙反应细胞。小组发现这个亚基的表达是由于在神经营养前馈回路中感觉神经支配提供的谷氨酸可用性增加。

此外，干扰这些神经元癌伪突触的谷氨酸-GRIN2D信号显著提高了体内存活。外周癌症神经元伪突触的发现可能为癌症神经科学指导的肿瘤治疗提供机会。

研究人员表示，癌症在神经元输入下茁壮成长。

附：英文原文

Title: Sensory neurons drive pancreatic cancer progression through glutamatergic neuron-cancer pseudo-synapses

Author: Lei Ren, Chunfeng Liu, Kaan ifciba, Markus Ballmann, Gerhard Rammes, Carmen Mota Reyes, Sergey Tokalov, Andreas Klingl, Jennifer Grünert, Keshav Goyal, Peter H. Neckel, Ulrich Mattheus, Benjamin Schoeps, Saliha Elif Yldzhan, Osman Ugur Sezerman, Nedim Can Cevik, Elif Arik Sever, Didem Karakas, Okan Safak, Katja Steiger, Alexander Muckenhuber, Kvan Grgülü, Zongyao Chen, JingCheng Zhang, Linhan Ye, Mohammed Inayatullah Maula Ali, Vijay K. Tiwari, Nataliya Romanyuk, Florian Giesert, Dieter Saur, Roland Rad, Roland M. Schmid, Hana Algül, Achim Krüger, Helmut Friess, Güralp O. Ceyhan, Rouzanna Istvanffy, Ihsan Ekin Demir

Issue&Volume: 2025-09-25

Abstract: Cancers thrive on neuronal input. Here, we demonstrate the presence of pseudo-synaptic connections between sensory nerve endings and cancer cells in an extracerebral cancer, i.e., pancreatic ductal adenocarcinoma (PDAC). These synaptic sites exhibit a selective enrichment of the glutamatergic N-methyl-D-aspartate receptor (NMDA) receptor subunit NMDAR2D (GRIN2D) on the cancer cells, which turns PDAC cells responsive to neuron-derived glutamate and promotes tumor growth and spread. Intriguingly, neurons transform a subset of co-cultured PDAC cells into calcium-responsive cells via GRIN2D-type glutamate receptors at the neuron-cancer pseudo-synapses. We found that the expression of this subunit is due to the increased glutamate availability provided by sensory innervation in a neurotrophic feedforward loop. Moreover, interference with the glutamate-GRIN2D signaling at these neuron-cancer pseudo-synapses markedly improved survival in vivo. This discovery of peripheral cancer-neuron pseudo-synapses may provide an opportunity for cancer-neuroscience-instructed oncological therapies.

DOI: 10.1016/j.ccell.2025.09.003

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(25)00395-2