Tumor heterogeneity is recognized as an important way in which tumors are able to grow, invade surrounding tissue, metastasize and develop resistance to therapies.

But linking specific states to the overall biology of tumors has been a challenge.

"No one really knows, what does [heterogeneity] mean for the biology, because there simply hasn't been a toolkit," Varun Venkataramani told BioWorld Science.

In a paper from the August 4, 2022, print issue of Cell, now published online, Venkataramani and his colleagues have described such a toolkit, and used their methods to show that in glioblastomas, invading cells are neuronal progenitor-like.

Venkataramani is a clinician at Heidelberg University Medical School, a researcher in its experimental neuro-oncology group, and the lead author of the Cell paper.

"What we offer is a methodological and also a conceptual framework," he said. "If we change certain cell states, how does it change tumor biology?"

Glioblastomas are among the deadliest cancer types there are, in part because they are highly invasive, which makes them impossible to remove surgically.

"You cannot resect everything. The disease always recurs, because it's already invaded into the same [brain] hemisphere, and also the contralateral hemisphere," Venkataramani said. "And the remaining parts are therapeutically resistant."

Previous studies had identified two populations of glioblastoma cells. One population forms an electrically interconnected network, via structures called microtubes. That interconnection contributes to the drug resistance of its member cells.

Not all cells are part of this interconnected network, however, and whether brain invasion is driven by cells in the network or by individual cells had been unclear.

In their experiments, Venkataramani and his colleagues used a combination of long-term imaging and RNA sequencing to demonstrate that "invading cells are neuronal progenitor-like... cells which hijack neuronal developmental mechanisms on a molecular level," he said.

Furthermore, such cells received synaptic connections from neurons that stimulated their migration, providing additional evidence for the importance of neuronal influences on tumors. Neurons are being recognized as a regulator of tumors, especially but not exclusively in the brain. Some researchers argue that the neuronal regulation of tumors and the microenvironment should be considered a new hallmark of cancer.

Venkataramani and his colleagues, too, "come from... a very cancer-neuroscience perspective on this disease," he said. "The nervous system plays a critical role for tumor initiation and tumor progression," and the findings provide "one puzzle piece of this emerging field of cancer neuroscience."

As the individual cells invaded, neuronal input stimulated the formation of tumor microtubes in those cells, which enabled them to connect both to brain cells and to each other, thus becoming part of a network.

The neuronal synapses on tumor cells used the neurotransmitter glutamate for signaling, and the tumor cells expressed a type of glutamate receptor called the AMPA receptor. When the investigators used the epilepsy drug perampanel, which they had used in earlier studies to reduce glioma proliferation, they showed that such treatment also reduced glioma invasiveness in animal studies, providing a possible approach to translating the findings clinically.

Scientifically, Venkataramani said, the work is also "a starting point for us to understand, what does the tumor connectome look like?"

"People might think about these tumors as single cells dividing uncontrollably," he said. But "it's a much more complex system. The sociology of these systems, they need to be studied much more."