Electrical and Synaptic Integration of Glioma Into Neural Circuits

High grade gliomas(HGG) are the leading cause of central nervous system cancer related deaths in both children and adults. Gliomas are basically a heterogeneous mix of tumours of astrocytes(astrocytoma - Glioblastoma multiforme) and/or tumours of oligodendrocytes (oligodendrogliomas) as well as tumours of ependymal cells (ependymoma).

Glioma progression is regulated not only by cell-intrinsic mechanisms, but also by important microenvironmental dependencies. Neurons in the tumour microenvironment form a crucial component for glioma proliferation and regulate malignant growth in an activity-dependent manner through the release of neuroligin-3 (NLGN3), indicating their fundamental role in glioma pathophysiology.

However, NLGN3 release is just a small part of a puzzle, that is insufficiently explained by stimulation of classical oncogenic signalling pathways alone. Hence there was a need to discuss the interplay of the glioma with the neurons at the much more fundamental level of synaptic signalling and neuroplasticity.

The special aspect of Gliomas, especially oligodendrogliomas is their phenotypic similarity to OPCs (Oligodendroglial Precursor Cells). The OPCs, as their name suggests, are not only the precursors to oligodendrocytes and glial cells, but also have postsynaptic receptors for synaptic signalling with surrounding neurons. This merits the hypothesis that the HGGs could also be having postsynaptic receptors which could be used for synaptic signalling with the neurons in the tumour microenvironment.

To conclusively prove the same, this paper took a plethora of approaches.

First they analysed the synaptic gene expression through single cell transcriptomic datasets, and found broad expression of postsynaptic structural genes, specifically of glutamate receptor genes in malignant glioma cells. Affirmingly, the synaptic enrichment was majorly seen in the glioma cells that most closely resembled OPC's.

Having established that primary glioma cells express a repertoire of synaptic genes, they then analysed whether structural synapses are actually formed between glioma cells and neurons in the tumour microenvironment.

Using immunohistochemistry, they proved that NLGN3 was essential for synapse formation between afferent neurons and glioma cells. Coupling whole cell patch clamp recordings of the glioma cells with simultaneous stimulation of surrounding neurons led them to find rapid inward depolarising currents, in the glioma cells characteristic of EPSPs, which were later revealed to be AMPA receptor- dependent postsynaptic currents.

Fascinatingly, using calcium imaging, they discovered that the depolarization in the glioma cells was being transferred by ion flow through gap junctions to other cells in the connected tumor cell networks in response to neuronal stimulation, indicating that a single afferent neuron could depolarise a huge gliomal network, and thereby gliomas were getting integrated into the electrical communication network of the brain.

Using optogenetic experiments, it was proved that the synaptic signalling is essential for tumour growth and proliferation. Add to this that the synaptic signalling gets stronger as the tumour keeps growing, by repeated feedback activation, an inherent concept for the development of neuroplasticity (neurons that fire together, wire together). However, by pharmacologically blocking the synaptic signaling, glioma growth could be inhibited and the lifespan could be extended.

This seemingly characteristic feature of the HGGs could have huge therapeutic implications, not only in the treatment of brain cancers, but also lead to insight for exploiting the neural regulation of tumors in prostate, pancreatic, skin and gastric cancers.

By blocking synaptic signalling pathways, through pharmacological and genetic interventions, we could essentially stop the tumour nourishment and growth, thus developing an approach which is quite unconventional to earlier tumour targeting methodologies.