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Ren, L.* ; Liu, C.* ; Çifcibaşı, K.* ; Ballmann, M.* ; Rammes, G.* ; Mota Reyes, C.* ; Tokalov, S.* ; Klingl, A.* ; Grunert, J.* ; Goyal, K.* ; Neckel, P.H.* ; Mattheus, U.* ; Schoeps, B.* ; Yıldızhan, S.E.* ; Sezerman, O.U.* ; Cevik, N.C.* ; Sever, E.A.* ; Karakas, D.* ; Safak, O.* ; Steiger, K.* ; Muckenhuber, A.* ; Görgülü, K.* ; Chen, Z.* ; Zhang, J.* ; Ye, L.* ; Maula Ali, M.I.* ; Tiwari, V.K.* ; Romanyuk, N.* ; Giesert, F. ; Saur, D.* ; Rad, R.* ; Schmid, R.M.* ; Algül, H.* ; Krüger, A.* ; Friess, H.* ; Ceyhan, G.O.* ; Istvanffy, R.* ; Demir, I.E.*

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

Cancer Cell, DOI: 10.1016/j.ccell.2025.09.003 (2025)
Verlagsversion DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Grin2d ; L-glutamate ; Nmdar ; Glutamatergic Receptor ; Innervation ; Neural Invasion ; Pancreatic Cancer ; Synapse
ISSN (print) / ISBN 1535-6108
e-ISSN 1878-3686
Zeitschrift Cancer Cell
Verlag Cell Press
Verlagsort Cambridge, Mass.
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Developmental Genetics (IDG)