Deciphering and Targeting the Synapses between Cancer Cells and Neurons in Pancreatic Cancer

Objective

The nervous system has recently been identified to play a central role in cancer pathogenesis, and this discovery has given birth to the burgeoning field of “cancer neuroscience”. Neurons and cancer cells outside the brain are known to communicate over paracrine signals, However, we recently discovered direct synaptic connections between sensory nerve endings and cancer cell membrane in a cancer outside the brain, i.e., pancreatic ductal adenocarcinoma (PDAC). These synaptic sites exhibit a selective enrichment of the glutamatergic NMDA receptor subunit GluN2D on the cancer cells, which enables PDAC cells to hijack the neurotransmitter L-glutamate over these cancer-neuron-synapses. This synaptic input not only aggravates tumor invasiveness and spread in vivo, but, surprisingly, also turns synaptically connected pancreatic cancer cells into electro-responsive, excitable cells via GluN2D-type glutamate receptors at the neuro-cancer synapses. Hence, we now have compelling evidence that pancreatic cancer cells are embedded into synaptically interconnected neuron-cancer networks in the pancreas. In the present study, we will perform the first real-time analysis of the emergence, evolution, function, and plasticity of synaptically interconnected neuron-cancer networks in PDAC. We will perform in vivo two-photon imaging focusing on these synapses in novel, human-like models of PDAC, will dissect their molecular operating mechanisms, and will assess the network activity over the neuron-cancer synapses directly in human PDAC specimens, but also in our novel “innervated organoids”. Finally, we will test the translational potential of the targeting this synaptic interconnection of pancreatic cancer cells with neurons in preclinical trials, coupled with in silico drug repurposing approaches. Therefore, through this comprehensive analysis of neuron-cancer synapses in PDAC, my vision is to open up new avenues for cancer neuroscience-instructed oncological therapies for PDAC.