Sensory neurons drive pancreatic cancer progression through glutamatergic neuron-cancer pseudo-synapses
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.
Authors
- Katja Steiger (ORCID: https://orcid.org/0000-0002-7269-5433)
- Sergey V. Tokalov (ORCID: https://orcid.org/0000-0003-0286-5721)
- Güralp O. Ceyhan (ORCID: https://orcid.org/0000-0002-3626-7423)
- Hana Algül (ORCID: https://orcid.org/0000-0002-5067-7031)
- Saliha Elif Yıldızhan (ORCID: https://orcid.org/0000-0003-3489-4666)
- Okan Safak (ORCID: https://orcid.org/0000-0002-9939-5924)
- Ulrich Mattheus
- Florian Giesert (ORCID: https://orcid.org/0000-0001-6825-8858)
- Kaan Çifcibaşı
- Elif Sever
- Kıvanç Görgülü (ORCID: https://orcid.org/0000-0002-1613-1422)
- Peter H. Neckel (ORCID: https://orcid.org/0000-0003-1976-0512)
- Didem Karakaş (ORCID: https://orcid.org/0000-0002-3781-6834)
- Rouzanna Istvánffy (ORCID: https://orcid.org/0000-0001-6652-9802)
- Linhan Ye (ORCID: https://orcid.org/0000-0001-8180-3152)
- Osman Uğur Sezerman (ORCID: https://orcid.org/0000-0003-0905-6783)
- Andreas Klingl (ORCID: https://orcid.org/0000-0001-8414-8317)
- Nedim Can Çevik
- Markus Ballmann
- Keshav Goyal (ORCID: https://orcid.org/0000-0002-4707-9524)
- Gerhard Rammes (ORCID: https://orcid.org/0000-0002-1698-4257)
- Mohammad Ali (ORCID: https://orcid.org/0000-0002-8907-4772)
- Alexander Muckenhuber (ORCID: https://orcid.org/0000-0002-0414-1797)
- Achim Krüger (ORCID: https://orcid.org/0000-0002-1517-9256)
- Benjamin Schoeps (ORCID: https://orcid.org/0000-0003-3934-0849)
- Vijay Tiwari (ORCID: https://orcid.org/0000-0003-0292-6635)
- Roland Rad (ORCID: https://orcid.org/0000-0002-6849-9659)
- Nataliya Romanyuk (ORCID: https://orcid.org/0000-0002-2838-6107)
- İhsan Ekin Demir (ORCID: https://orcid.org/0000-0001-8241-1871)
- Dieter Saur (ORCID: https://orcid.org/0000-0001-5874-0210)
- Chunfeng Liu
- JingCheng Zhang
- Roland M. Schmid (ORCID: https://orcid.org/0000-0002-5751-7313)
- Lei Ren (ORCID: https://orcid.org/0000-0003-2131-1601)
- Helmut Frieß
- Zongyao Chen (ORCID: https://orcid.org/0000-0002-4202-9579)
- Carmen Mota Reyes
- Jennifer Grünert
Institutions
- University of Southern Denmark (DK)
- German Cancer Research Center (DE)
- TUM Klinikum (DE)
- Affiliated Hospital of Southwest Medical University (CN)
- Institute of Bioinformatics and Systems Biology (DE)
- Czech Academy of Sciences, Institute of Experimental Medicine (CZ)
- Kent Hastanesi (TR)
- Acıbadem Adana Hospital (TR)
- Technical University of Munich (DE)
- University of Tübingen (DE)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Cancer Cell
- Published
- 2025-09-25
- DOI
- https://doi.org/10.1016/j.ccell.2025.09.003
- Citations
- 14
- Primary Topic
- Cancer, Stress, Anesthesia, and Immune Response
- Type
- article
- Field-Weighted Citation Impact
- 20.60