black-and-white brain scan showing white tumor
An MRI scan of the brain of a patient with glioblastoma

Glioblastomas are still incurable brain tumors, due in part to their particular invasiveness: They spread throughout the brain, and so cannot be removed entirely by surgery. Now, a study in mice published July 31 in Cell has identified a factor that drives this invasiveness, finding that one population of glioblastoma cells behaves like immature neurons, and—stimulated by input from the brain’s own neurons—pioneers the tumor’s spread into new brain regions. 

“The study is highly interesting,” says Andreas Bikfalvi, a biomedical researcher at the University of Bordeaux in France who was not involved in this study. “It really contributes to describing, for the first time, that neuronal input is driving invasion in glioblastoma cells.” 

In previous work, some of the study’s authors had shown that glioblastoma cells connect with each other via tumor microtubules. The new study’s first author, Varun Venkataramani, a brain tumor researcher at University Hospital Heidelberg and the German Cancer Research Center, describes these tumor microtubules as “neurite-like protrusions that form networks with other tumor cells.” However, glioblastoma cells are very heterogenous, and not all of them are well-connected. In addition, Venkataramani and colleagues had also shown that neurons send signals to glioblastoma cells through a special type of synapse, and that these signals drive tumor progression. “Now we wanted to bring all this together—the heterogeneity, the connectivity, and the functional aspects of invasion,” Venkataramani tells The Scientist. 

For the experiment, the researchers grafted bits of glioblastomas from human patients into mouse brains. Using a dye, SR101, that is taken up and distributed among connected glioblastoma cells but not by unconnected glioblastoma cells, the researchers were able to distinguish the different cell populations within those tumors. With the help of an AI algorithm, they followed single cells growing in mouse brains over time and found that the unconnected cells mimic molecular signatures, uncovered using single-cell RNA sequencing, that resemble immature neurons during development. There were also similarities between the glioblastoma cells and immature neurons in the ways in which the cells invaded the brain, including through branching migration, locomotion, and translocation. In short, the glioblastoma cells “behave like immature neurons that are not normally found in the adult brain,” says Venkataramani. 

Now we understand much better that different populations of the tumor are driving different biological functions.

—Varun Venkataramani, University Hospital Heidelberg and German Cancer Research Center

Following the glioblastoma cells over time as they invaded the brain, the researchers also uncovered a dynamic relationship between unconnected and connected glioblastoma cells. Unconnected cells are “pioneering cells” at the edge of the tumor that explore the brain. Once they have found a favorable spot, the unconnected cells transition into the connected cell type, forming a tight network with other connected glioblastoma cells. While the connected cells are more resistant to therapy than the unconnected pioneer cells, these networked cells can’t explore new regions. “Now we understand much better that different populations of the tumor are driving different biological functions,” Venkataramani explains. 

Finally, the researchers used a technique called patch-clamping to detect signalling between neurons and glioblastoma in culture, and found that glioblastoma cells receive input from neurons. Glioblastoma cells receiving neuronal input in a coculture with neurons had longer tumor microtubules and more branches than glioblastoma cells not receiving neuronal input. Thus, the authors argue that neuronal input increases the efficiency with which glioblastoma cells explore the brain, driving both invasion and progression. 

While Bikfalvi sees the paper as “highly interesting” and “very solid,” he cautions that there are “many players around . . . like matrix stiffness, blood vessels, the endothelia and so forth” that also play a role in cancer progression. “We don’t yet have the understanding [of] what, in the global context, is the major causal driver” of glioblastoma invasion. 

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Peter Hau, a neurooncologist at the University Hospital Regensburg in Germany who was not involved in the study, writes in an email to The Scientist that he expects “that this research will quickly fuel in several translational approaches and will certainly help to develop therapies in these devastating tumors.” In the study, the authors took a first step toward clinical applications, finding that an inhibitor of the type of receptors that receive the signal at the synapse between glioblastoma and nerve cells reduced the formation and branching of tumor microtubules in mice.