Sensory neurons drive pancreatic cancer progression through glutamatergic neuron-cancer pseudo-synapses
Lei Ren, Chunfeng Liu, Kaan Çifcibaşı, Markus Ballmann, Gerhard Rammes, Carmen Mota Reyes, Sergey V. Tokalov, Andreas Klingl, Jennifer Grünert, Keshav Goyal, Peter H. Neckel, Ulrich Mattheus, Benjamin Schoeps, Saliha Elif Yıldızhan, Osman Uğur Sezerman, Nedim Can Çevik, Elif Sever, Didem Karakaş, Okan Safak, Katja Steiger, Alexander Muckenhuber, Kıvanç Görgülü, Zongyao Chen, JingCheng Zhang, Linhan Ye, Mohammad Ali, Vijay Tiwari, Nataliya Romanyuk, Florian Giesert, Dieter Saur, Roland Rad, Roland M. Schmid, Hana Algül, Achim Krüger, Helmut Frieß, Güralp O. Ceyhan, Rouzanna Istvánffy, İhsan Ekin Demir
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.