Brain cancer can talk, and talking can help it grow

How do you talk to your friends? From texting and video calls to Snapchats and Instagram DMs, modern-day technology has provided enormous possibilities for instantaneous global communication. Alongside these endless means of internet conversation, an unnerving query has likely crossed your mind: What if someone was listening in on your conversations? What could they do with that information?

Just like you might talk to your friends through a text message that reaches them in a few seconds, the neurons in your brain talk to each other at a 580 miles per hour rate. The point of communication between two neurons is called a synapse, and neurons send electrical signals through synapses to talk to each other about what the rest of our body sees, smells, hears, feels, and tastes. One neuron can be connected to 10,000 other neurons through 1,000 trillion synapses. All these conenctions create a network of neurons carrying information in our brain. But what would happen if these electrical signals were hijacked? A paper published by Venkatesh et. al. 2019 shows how gliomas, which are deadly brain cancers, can take over the brain’s synaptic communication system to aid in their own growth.

Figure 1. The electron microscope image on the left shows a synapse (pink) right next to a glioma cell (green). The graph on right shows that around 10% of glioma cells had a synaptic structure

 Understanding how human glioma cells talk can be hard, because we can’t perform experiments on patients with brain cancer. So, to see if synapses can exist between glioma cells and neurons, the authors used a patient-derived glioma xenograft model. This means that they took glioma tumor samples from a human patient and directly transplanted them into mice that  could be studied in a laboratory. The authors kept track of which cells were healthy and which cells were tumorous by labeling the glioma cells with a protein that glows under an electron microscope. No one had ever shown that brain cancer could talk to healthy human neurons, so the authors were surprised to see that there were synapses on 10% of the glowing glioma cells (Fig. 1). They saw that there were two types of signals sent between glioma cells and neurons. Firstly, they found signals that looked just like those sent amongst neurons themselves. Interestingly, they also found signals that were longer in duration and could be amplified throughout larger networks of glioma cells via connections called gap-junctions.

Figure 2. The graph on the left shows that electrically stimulating the glioma cells leads to more proliferation, or growth, of the glioma compared to the “mock” stimulation. The images on the left show that with more stimulation, there are more tumor cells (bright white spots).

Next, the authors wanted to see if the synapses and gap-junctions between the glioma cells and healthy neurons actually mattered when it came to tumor growth and patient survival. To do so, they used optogenetics, a technique that allows scientists to control the activity of specific groups of cells in the brain. To do this, the authors genetically modified the neuron and glioma cells to express a protein called opsin, which is activated by blue light. Then, by shining the blue light for different durations, they could control how many electrical signals were sent between neurons and glioma cells. They found that mice that had more electrical signals sent between neurons and glioma cells had increased tumor growth and worse survival (Fig. 2). They also found that when they used drugs that are known to block synaptic and gap-junction signals, the glioma cells did not grow as large, and the mice had better survival.

 Ultimately, the findings in this paper greatly contribute to our understanding of how deadly brain tumors can attack our brain. We now know that brain tumor cells can talk to healthy neurons through synapses and gap-junctions, and that they use the hijacked electrical communication signals to aid in their own mission of generating more glioma cells to invade healthy brain tissue. Though this information may seem disheartening at first, the authors’ discovery also helps expand treatment options for gliomas. We can now start targeting the synaptic and gap-junction based conversations between gliomas and healthy neurons to stop them from talking, slow down tumor growth, and improve patient survival.

Edited by Manasi Iyer

References:

Venkatesh, H.S., Morishita, W., Geraghty, A.C. et al. Electrical and synaptic integration of glioma into neural circuits. Nature 573, 539–545 (2019). https://doi-org.stanford.idm.oclc.org/10.1038/s41586-019-1563-y