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How synapse formation drives brain cancer growth

last modified Sep 27, 2019 01:20 PM
A study just published in Nature, by a team including Hugh Robinson of PDN, has shed new light on how glutamate receptor ion channels are involved in metastasis of cancer to the brain, showing that cancer cells which express growth-promoting glutamate receptors integrate themselves into neuronal synapses to obtain activating glutamate.

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, via activation of downstream calcium signalling. Work by Hugh Robinson and collaborators showed that this works through an “autocrine” signalling loop, by which the cancer cells activate their own NMDARs by releasing glutamate themselves, without requiring the collaboration of other cell types (Li and Hanahan, 2013; Robinson and Li, 2017; Li et al., 2018).

In this new study (Zeng et al., 2019; Barria, 2019), an international collaboration led by Douglas Hanahan (EPFL, Switzerland), examined breast cancer cells metastasizing to the brain, and found that they similarly express invasion-promoting NMDARs. However, instead of an autocrine mechanism, cancer cells make use of glutamate released by neurons at synapses, by wrapping tightly around the synapse in a “pseudo-tripartite” configuration, in effect forming an excitatory connection between neurons and the brain-metastatic cancer cells. Through genetic knockdown experiments, the resulting NMDAR signalling was shown to drive metastatic colonization - the ability of brain metastases to become established and grow in the brain microenvironment.

Two companion papers published in the same issue of Nature from groups at Stanford and Heidelberg show that glioma, a kind of brain tumour arising within the brain, similarly forms synaptic connections with neurons (using AMPARs rather than NMDARs) which drive primary brain tumour progression. Together, these papers show that tumour cells in the brain integrate into, and feed off, synaptic communication in the brain’s network of neurons.

References

Zeng Q, Michael IP, Zhang P, Saghafinia S, Knott G, Jiao W, McCabe BD, Galván JA, Robinson HPC, Zlobec I, Ciriello G, Hanahan D (2019) Synaptic proximity enables NMDAR signalling to promote brain metastasis. Nature 573:526–531

Barria A (2019) Dangerous liaisons as tumour cells form synapses with neurons. Nature 573:499–501.