Role of direct neuron-tumour cell synapses for the progression of melanoma brain metastases and primary melanoma

• Applicant: Dr. Varun Venkataramani
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Hematology, Oncology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 458528657

Brain metastasis is a frequent and devastating complication of many cancer entities, with increasing incidence. The outgrowth of brain metastases is determined by cells of the brain microenvironment including astrocytes and neurons. Previously, it has been shown that perisynaptic contacts of breast cancer brain metastasis can promote tumour growth by NMDA receptor signalling. Recently, we found glutamatergic synapses between neurons and primary brain tumours that drive tumour progression and invasion. Here, I want to investigate whether such direct, bona-fide glutamatergic synapses are formed onto brain metastases of another prominent cancer entity, melanoma, and if these synapses have similar effects on the progression of melanoma brain metastases. Furthermore, I want to investigate whether the peripheral nervous system forms synaptic connections onto primary melanoma cells as well. This could help to further our understanding whether neuron to tumour synaptic communication is a phenomenon relevant for the progression of melanoma in general or restricted to the unique microenvironment of the brain.Genetic and pharmacological perturbation of AMPA receptors in tumour models of melanoma and its effect on the number of brain metastases and overall brain metastatic burden as well as its impact on the progression of primary melanoma will be determined. These findings have the potential to show a novel and biologically relevant direct synaptic communication between neurons and melanoma cells with potential clinical implications. Furthermore, the findings of this study may support synaptic neuron to tumour communication as a feature generally promoting tumour progression.

• DFG Programme: Research Grants