Sensory neurons drive pancreatic cancer progression through glutamatergic neuron-cancer pseudo-synapses
Menée à l'aide de lignées cellulaires et de modèles murins d'adénocarcinome canalaire du pancréas, cette étude met en évidence l'existence d'une signalisation synaptique entre les neurones sensoriels et les cellules cancéreuses puis démontre le rôle de cette signalisation dans la croissance et la propagation tumorales
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.
Cancer Cell , article en libre accès, 2025