Scientists Uncover How Glioma Hijacks Brain Signals to Grow

Of the many forms cancer can take, tumours that develop in the brain may be among the most challenging to treat.

Glioma is one particularly formidable type of tumour. These malignant growths develop from glial cells, or their precursors, in the brain or spinal cord. Its most severe form – glioblastoma – has a 5-year survival rate of only 5 to 7 percent.

One reason gliomas are so hard to treat is that they actively harness vital processes in the brain to sustain their own growth.

In a new study published in Nature Neuroscience, researchers have identified one mechanism that enables this exploitation. They believe the finding may open up new possibilities for treatment.

How glioma uses the brain's support cells

Glial cells are non-neuronal cells forming the brain's support network. They carry out a broad variety of functions that assist neurons, including insulating, protecting and nourishing them.

Among these cells are oligodendrocytes, which create the fatty myelin coating that insulates nerve fibres. Oligodendrocytes arise from oligodendrocyte precursor cells, or OPCs, which respond to neuronal activity.

Many gliomas are believed to originate in OPCs, and these tumours preserve some of the precursor cells' capacity to react to neuronal activity. Earlier research found that active neurons release a protein called neuroligin-3 (NLGN3), which encourages glioma cells to proliferate.

But precisely how glioma cells sense NLGN3 and turn it into a signal for growth had remained unknown.

NLGN3, CSPG4 and PIEZO1 drive glioma growth

To investigate, researchers led by bioengineer Yoon Seok Kim of Stanford University, now at the Swiss Federal Institute of Technology Lausanne, and Stanford neuroscientist Shawn M. Gillespie grew patient-derived human glioma cells in the laboratory.

They used NLGN3 as bait, examining which proteins in the glioma-cell membranes would bind to it.

One protein was especially notable: chondroitin sulphate proteoglycan 4 (CSPG4), found in abundance on the surfaces of both OPCs and glioma cells.

When NLGN3 bound to CSPG4, the membrane of the glioma cell physically became tighter.

This mechanical alteration helps set off events within the cell. The rise in membrane tension activates an ion channel called PIEZO1. Turning a physical force into a biological response in this way is called mechanotransduction.

The resulting movement of ions activates signalling within the cell that promotes glioma-cell proliferation.

The team next examined whether PIEZO1 genuinely affected glioma growth. Through gene editing, they created patient-derived glioma cells without PIEZO1 and implanted them into mouse brains. Control experiments used otherwise comparable cells in which PIEZO1 remained intact.

After four weeks, the glioma cells lacking PIEZO1 were proliferating significantly less than cells with the channel intact.

The pathway's normal role in OPCs

The researchers then sought to understand why the NLGN3-CSPG4-PIEZO1 machinery exists at all.

Returning to healthy OPCs, they discovered that the same system operates there. NLGN3 binds to CSPG4, activating PIEZO1, although the signalling produced within the cell has a different outcome.

Instead of making OPCs proliferate, this pathway keeps cells as immature OPCs, preventing their maturation into oligodendrocytes. This could help the brain retain a healthy supply of OPCs.

To verify this, the researchers genetically removed NLGN3 from OPCs in mice. They found that OPC reserves in the corpus callosum fell by around 30 percent.

The cancer cells, then, are not creating this machinery from nothing. Instead, they commandeer and repurpose the brain's ordinary machinery for their own ends.

That gives scientists a possible new weakness in glioma to explore: its reliance on mechanosensitive signalling.

Related: This Common Drug Seems to Fight One of The Deadliest Brain Cancers

Yet the finding also illustrates why cancer can be so hard to treat: caution will be essential. Since healthy brain cells also use this machinery, converting the discovery into a treatment could require a way to inhibit the cancer without disturbing the normal OPC population.

"The findings presented here underscore a critical role for an NLGN3-CSPG4-mechanotransduction pathway in the interplay between neuronal activity and glioma progression, advancing understanding of a key mechanistic pathway by which gliomas exploit neuronal signals for growth," the researchers write.

"The identification of mechanotransduction as an important mediator in this process suggests new therapeutic opportunities, highlighting the potential for targeting mechanosensitive pathways in glioma and possibly in other cancers."

The findings were published in Nature Neuroscience.

This article was fact-checked and edited by Peter Dockrill. While we take pride in our process, we are only human. If you notice an error, please let us know.