Identification of Neurons Connected to Gliomas Revealed for The First Time, Aiding The Development of New Glioma Treatments

Gliomas are the most common type of brain cancer, including the deadliest form, glioblastoma. Every week, Harvard Medical School neuro-oncologist Annie Hsieh treats patients with gliomas. After Hsieh's fellow neurosurgeons remove a glioma with surgery, it often appears that no cancer cells are left. Radiation and other treatments may follow. However, gliomas often recur, not only in the original site but also in distant parts of the brain. This can harm the nervous system and, in some cases, lead to death.

What exactly happens in the brain that prompts these tumors to regrow there, but rarely in other parts of the body? The question has puzzled scientists for decades and made gliomas one of the most difficult cancers to treat.

Now, Hsieh and collaborators at Harvard Medical School have filled in part of that puzzle, revealing for the first time the types of neurons in the brain that connect to gliomas. Their dissection of the identity and properties of these glioma-innervating neurons (GINs) in mice provides new insights into the drivers of how this cancer forms and spreads in the brain and how to develop new therapeutic strategies to prevent cancer recurrence. The findings were published online in the journal PNAS on December 4, 2024, with the title "Widespread neuroanatomical integration and distinct electrophysiological properties of glioma-innervating neurons."

"This is the first step, providing an intuitive explanation for why this tumor is ubiquitous in the brain," said Hsieh. "We can now see where the connected neurons originate, study how they integrate with gliomas, and look for opportunities to interrupt growth."

This study overcomes long-standing barriers to visualizing and analyzing neurons connected to gliomas and demonstrates a way to more broadly advance the study of interactions between tumors and the nervous system.

How gliomas invade neural networks

Gliomas originate from glial cells, which play an important role in building and maintaining neural circuits. Scientists already knew that neurons form synapses with glioma cells, but they could not see where the other ends of these neurons (cell bodies) were located in the brain. This obscured the identity of these neurons.

Hsieh and her team successfully tracked the source of GINs using a rabies virus. The rabies virus used was modified to infect only specific cells of interest and light up these cells after entering them. The rabies virus traveled from tumor cells and entered neurons connected to them. They injected human glioma cells into the brains of mice and waited for neurons to connect to the tumor. Then, they used the rabies virus to light up the cells of interest. Soon, they had an image that illuminated the mouse brain and showed all the glowing neurons leading to the glioma. The resulting image showed that the glioma connected to the existing neuronal wiring patterns.

"The neuronal wiring was already there, and the glioma just connected to it. The glioma hijacked what was already there instead of forming its own arbitrary connections," said Hsieh.

The authors observed that these neurons came from all over the brain. "They travel all the way from the brain to the tumor," Hsieh said. "It's fascinating how neural networks work and how these super scary tumors integrate with and infiltrate the entire nervous system."

Uncovering the secret identity of neurons

The authors found that GINs extending from distant parts of the brain were mostly of the type that make glutamate, a major brain chemical that makes neurons excited. This finding is consistent with previous observations that neuronal excitation spurs glioma growth and that communication between neurons and gliomas involves glutamate. However, a subset of GINs that reached far into the brain showed that they make both glutamate and another chemical that inhibits neuronal activity, gamma-aminobutyric acid (GABA). In some brain regions, GINs from near the tumor site appeared to express mostly GABA.

Figure 1. Transsynaptic tracing of GINs using RV. (Hsieh A L, et al., 2024)

These findings suggest that the neurons that interact with glioma cells are more diverse than previously appreciated. What this means for tumor growth and spread is unclear. "We found that tumors have connections everywhere," Hsieh said. "Whether these connections provide them with pathways to everywhere is a question we need to investigate."

The Hsieh team probed the electrical properties of the GINs and found that they differed in some ways from similar neurons in brains without gliomas. Such differences in interactions between normal neurons and GINs, or between neurons and neurons or between neurons and gliomas, provide valuable clues for researchers like Hsieh as they search for ways to intervene in cancer progression while preserving normal function.

There is a pressing need to develop treatments for gliomas, Hsieh says. She notes that scientists have tried to treat gliomas with drugs used to treat other types of cancer, but most have failed. "By uncovering the drivers of glioma-neuron interactions and identifying unique mechanisms, we can explore strategies to interrupt them, potentially stopping the tumor in its tracks and preventing its recurrence," Hsieh says.

While Hsieh knows it will be many years before the lab's discoveries are translated into treatments that benefit her glioma patients and others around the world, she is optimistic that these latest insights will help advance the field.

Reference

Hsieh A L, et al. Widespread neuroanatomical integration and distinct electrophysiological properties of glioma-innervating neurons. Proceedings of the National Academy of Sciences, 2024, 121(50): e2417420121.