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

The results provide significant insights into the role of Grin2D in regulating the secretion of neurotrophic factors that promote neuritogenesis. Transcriptomic analysis of orthotopically transplanted PDAC cancer cells with a knockout of the NMDA receptor subunit Grin2D, along with dorsal root ganglia (T8–T12) innervating the pancreas, strongly supports this conclusion. Furthermore, RNA-Seq analysis of tumor and ganglion biopsies from PDAC patients was performed to validate the identified gene candidates in a human context. This study tested the hypothesis that neuronal glutamate drives pancreatic cancer progression via glutamate-mediated GluN2D signaling at the cancer-neuron pseudo-synapses. For the analysis, murine KPC cancer cells with Grin2d-KO were orthotopically transplanted into C57BL/6N wild-type mice. As controls, WT KPC cells were used. After transplantation, RNA-seq was performed on the tumors of these mice from each group, along with dorsal root ganglia (T8–T12) innervating the pancreas. Furthermore, RNA-seq was also conducted on tumor and ganglion biopsies from PDAC patients.