Submitted by Dr R. Inchingolo on Thu, 05/04/2018 - 12:16
Two studies published in Open Biology and Cancer Cell, co-authored by Hugh Robinson, have shed new light on how glutamate receptor ion channels are involved in cancer progression
NMDA glutamate receptors (NMDARs) are well known as synaptic ion channels in the central nervous system, mediating neuronal excitation and calcium influx which are critical in synaptic plasticity, brain development and response to injury. Recently, however, it was shown that NMDARs also promote growth and invasiveness in some cancers, with evidence pointing to an “autocrine” signalling loop, through which the cancer cells activate their own NMDARs by releasing glutamate themselves, without requiring the collaboration of other cell types. The calcium influx through the activated NMDARs then switches on downstream processes causing increased invasiveness.
In the first study, published in Open Biology, Hugh Robinson and Leanne Li (MIT) provide detailed insight into this autocrine mechanism, by using patch-clamp recording to demonstrate the activation of single NMDAR molecules in the membranes of pancreatic neuroendocrine tumour (PanNET) cells. By perfusing the interior of cells with glutamate-containing solutions, they showed how cells achieve autocrine signalling by releasing the glutamate which activates their own NMDA receptors. They also demonstrated a novel mechanism of activation of NMDA receptors in tumour cells, using glutamate released from necrotic cell death, which involves uncontrolled rupture of the cell membrane and release of cytoplasmic contents, including high levels of glutamate, into the extracellular environment.
In the second study, published in Cancer Cell, by an international collaboration led by Douglas Hanahan (EPFL, Switzerland) and including Hugh Robinson, the genetic modulation of NMDAR signalling was investigated, to try to understand how this invasive and growth-promoting pathway is switched on in cancer. This study discovered that GKAP, a scaffolding protein associated with NMDARs at postsynaptic sites in the nervous system, has a pivotal role in regulating NMDAR pathway activity in pancreatic cancer. Using genetic knockdown of GKAP, and pharmacological inhibition of NMDARs, expression profiles associated with NMDAR-GKAP signalling and its inhibition were identified. Transcriptome signatures in tumours with low or inhibited NMDAR pathway activity were found to be associated with favourable patient prognosis in several cancer types, giving hope that targeted inhibition of NMDAR-GKAP signalling can benefit patients in the future.
References:
Hugh Robinson and Leanne Li (2017), Autocrine, paracrine and necrotic NMDA receptor signalling in mouse pancreatic neuroendocrine tumour cells. Open Biol. 7: 170221. http://dx.doi.org/10.1098/rsob.170221
Leanne Li, Qiqun Zeng, Arjun Bhutkar, José Galván, Eva Karamitopoulou, Daan Noordermeer, Mei-Wen Peng, Alessandra Piersigilli, Aurel Perren, Inti Zlobec, Hugh Robinson, M. Luisa Iruela-Arispe, and Douglas Hanahan (2018), GKAP acts as a genetic modulator of NMDAR signaling to govern invasive tumor growth, Cancer Cell 33, 1–16, https://doi.org/10.1016/j.ccell.2018.02.011