First look at the interplay between neurons and tumors sheds light on formation, spread
Every week, Harvard Medical School neuro-oncologist Annie Hsieh treats patients with gliomas — the most common type of brain cancer, including the deadliest, glioblastoma.
After Hsieh’s neurosurgeon colleagues remove a glioma surgically, it often looks like none of the cancer is left behind, she says. Radiation and other treatments may follow. Yet gliomas tend to come back, not just at the original site but in distant parts of the brain, threatening neurological harm and, in some cases, death.
What happens in the brain to encourage these tumors to regrow there, while only rarely appearing in other parts of the body? The question has stumped scientists for decades and made gliomas one of the hardest-to-treat cancers. It’s also a mystery that physician-scientist Hsieh has long wanted to solve.
Now, she and HMS collaborators have filled in a piece of the puzzle by providing the first look at the types of neurons in the brain that connect to gliomas. The team’s findings were reported Wednesday in PNAS.
Profiling the identities and properties of such glioma-innervating neurons in mice provides new insights into what drives these cancers’ formation and spread in the brain. The findings can also help researchers
“This is a first step that provides a visual explanation for why the tumors can be everywhere in the brain,” said Hsieh, first author of the study and HMS instructor in neurology at Mass General Hospital. “We can now see where the connected neurons originate, study how they integrate with gliomas, and look for opportunities to interrupt growth.”
The study overcomes a long-standing obstacle to visualizing and analyzing the neurons that link with gliomas and demonstrates a way to advance the study of interactions between tumors and the nervous system more broadly.
Hsieh conducted the work when she was a research fellow in neurobiology in the lab of Bernardo Sabatini and in cell biology in the lab of Marcia Haigis in the Blavatnik Institute at HMS. Haigis and Sabatini are co-senior authors of the study.
How gliomas hack the network
Gliomas arise from glia, cells that perform essential functions in sculpting and maintaining neural circuits. Scientists already knew that neurons form synapses onto glioma cells, but they couldn’t see where the other ends of those neurons (the cell bodies) are in the brain. That obscured the neurons’ identities.
Hsieh and team successfully traced the glioma-innervating neurons back to their sources using a rabies virus engineered to infect only specific cells of interest and to light up those cells when it gets in. The virus travels from the tumor cell back through the neuron that connects to it.
The researchers injected human glioma cells into the brains of mice and waited for neurons to connect with the tumors. They then applied the rabies virus to light up cells of interest. Soon, they had a picture illuminating the mouse brains showing all the glowing neurons that led to the glioma.
The maps revealed that the gliomas hook into existing patterns of neuronal wiring.
“The wires are already there; the gliomas just connect to them,” Hsieh said. “They hijack what’s already in place rather than forming their own arbitrary connections.”