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

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

Ren, Lei; Liu, Chunfeng; Çifcibaşı, Kaan; Ballmann, Markus; Rammes, Gerhard; Mota Reyes, Carmen; Tokalov, Sergey; Klingl, Andreas; Grünert, Jennifer; Goyal, Keshav; Neckel, Peter H; Mattheus, Ulrich; Schoeps, Benjamin; Yıldızhan, Saliha Elif; Sezerman, Osman Ugur; Cevik, Nedim Can; Sever, Elif Arik; Karakas, Didem; Safak, Okan; Steiger, Katja; Muckenhuber, Alexander; Görgülü, Kıvanç; Chen, Zongyao; Zhang, JingCheng; Ye, Linhan; Maula Ali, Mohammed Inayatullah; Tiwari, Vijay K; Romanyuk, Nataliya...     »

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.      «

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,...     »