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NMDA glutamate receptor activation by necrotic cell death in cell survival and invasiveness

Supervisor: Hugh Robinson, Randall Johnson (co-supervisor)

NMDA receptors (NMDARs) play a key role in the CNS, acting as synaptic receptor ion channels which mediate calcium influx in neurons and synaptic plasticity, and also profoundly influencing neuron development and survival. Functional NMDAR signalling has also been reported in tissues outside the CNS, for example in skin keratinocytes during re-epithelialization following skin injury. It has been shown that many cancer cell lines and tumours express GluN1 and GluN2B NMDA receptor mRNA and protein, including small-cell lung cancer (SCLC) (North et al., 2010). Recent studies (Li and Hanahan, 2013, Li et al, manuscript in preparation) provide comprehensive evidence that NMDAR signalling promotes invasive growth of pancreatic neuroendocrine tumours (PanNETs), and that an upregulated NMDAR pathway is associated with poor patient prognosis in various cancer types. In PanNETs, NMDARs activate downstream calcium-dependent CaMK and MEK-MAPK signalling, and NMDAR blockers inhibit cancer cell invasiveness and survival. Thus, it is increasingly suggested that NMDARs can play a major role in cancer progression, especially in promoting invasiveness of tumour cells through surrounding normal tissue. However, the detailed physiological mechanisms of this have not been elucidated. Recently, we have shown that necrosis of PanNET cells causes a massive release of glutamate, strongly activating NMDARs in surrounding cells in culture. This project will use patch-clamp electrophysiology and optical measurement of calcium and glutamate to quantify the function of NMDARs in a panel of mouse SCLC cell lines, and to study how NMDARs in SCLC cells may also be activated by autocrine, paracrine and necrotic release of glutamate. In collaboration with the Johnson lab, we will also explore the novel approach of carrying out patch-clamp electrophysiology in acutely-isolated, ex-vivo tumour tissue slices, using techniques commonly applied in neuroscience for studying electrophysiology in brain slices. This will be used to validate the findings from 2D cultures, but in a context of much more realistic tissue architecture and cell development. The application of electrophysiological approaches to investigate invasiveness brings together two fields to give new insights into the factors governing how cells survive and die, and also has the potential to develop novel therapeutic approaches.

Relevant references

Li, L., and Hanahan, D. (2013). Hijacking the neuronal NMDAR signaling circuit to promote tumor growth and invasion. Cell 153, 86–100.

North, W.G., Gao, G., Jensen, A., Memoli, V.A., and Du, J. (2010). NMDA receptors are expressed by small-cell lung cancer and are potential targets for effective treatment. Clin. Pharmacol. Adv. Appl. 2, 31–40.

Robinson, H.P.C. and Li, L. (2016) Electrophysiology of autocrine and paracrine NMDA receptor signalling in invasive mouse pancreatic neuroendocrine tumour cells. NCRI Cancer Conference 2016, Liverpool, UK.

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