Journal Article

DKFZ-2025-01971

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Sensory neurons drive pancreatic cancer progression through glutamatergic neuron-cancer pseudo-synapses.

Ren, L.DKFZ* ; Liu, C. ; Çifcibaşı, K. ; Ballmann, M. ; Rammes, G. ; Mota Reyes, C.DKFZ* ; Tokalov, S.DKFZ* ; Klingl, A. ; Grünert, 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.DKFZ* ; Chen, Z. ; Zhang, J. ; Ye, L. ; Maula Ali, M. I. ; Tiwari, V. K. ; Romanyuk, N. ; Giesert, F. ; Saur, D.DKFZ* ; Rad, R.DKFZ* ; Schmid, R. M. ; Algül, H. ; Krüger, A. ; Friess, H.DKFZ* ; Ceyhan, G. O. ; Istvanffy, R.DKFZ* ; Demir, I. E.DKFZ*

2025
Cell Press Cambridge, Mass.

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Please use a persistent id in citations: doi:10.1016/j.ccell.2025.09.003

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.

Keyword(s): GRIN2D ; L-glutamate ; NMDAR ; glutamatergic receptor ; innervation ; neural invasion ; pancreatic cancer ; synapse

Note: 2025 Dec 8;43(12):2241-2258.e8

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Contributing Institute(s):

1. DKTK Koordinierungsstelle München (MU01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 50 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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