Glioblastoma’s Shape-Shifting Nature

HSCI scientists investigate treatment-resistant brain cancer using single-cell sequencing

brain cancer
A single glioblastoma tumor contains four cell types that can change into one another. Image credit: Leslie Gaffney/Aviv Regev lab.

Glioblastoma, an aggressive cancer, starts in the brain’s supporting glial cells and infiltrates healthy brain tissue. Most children die of this highly malignant tumor within one to two years of diagnosis.

Glioblastoma treatment involves surgical removal, radiation, and chemotherapy — a grueling regime with long recovery times. But no existing chemotherapy treatment actually improves a patient’s chances of survival. To better understand why, Harvard Stem Cell Institute (HSCI) scientists used sequencing techniques to study the disease.

The study was led by Mario Suvà, M.D., Ph.D., leader of HSCI’s cancer program. The researchers found that regardless of what genetic mutation causes glioblastoma, it can readily shift among four distinct cell types, each of which may need to be targeted separately during treatment. The findings were published in the journal Cell.

Profiling a tumor, cell by cell

In both children and adults, glioblastoma can take many forms — hence the cancer’s full name, glioblastoma multiforme. Until now, scientists thought that all tumor cells are the same within a given patient.

That turns out not to be true. The tumor is a mosaic.

While DNA is hard-wired, the RNA “transcriptome” is more like software, providing a readout of what genes are turned on and what proteins the cell is making — revealing what the cell is doing and what state it’s in. In this study, the researchers analyzed tumors from eight children and 20 adults, going cell by cell.They profiled more than 24,000 individual cells, sequencing the RNA of each one.

“If you look at single cells, they’re very different from one another. Some are more immature, stem-like cells, some are differentiating cells, and some are mature cells that are not even dividing anymore,” said Mariella Filbin, M.D., Ph.D., co-lead author of the study and a pediatric neuro-oncologist at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center.

Morphing among cell types

More ominously, the four cell types could all change into each other. The study showed that glioblastomas are highly “plastic” — their cell types readily morphing over time and when exposed to cancer treatments. When the researchers injected any of the four types of patient tumor cells into mice, they all formed tumors containing all four cell types.

“This explains the failures of single-target drugs,” said Filbin. “The tumors can ‘become’ something else and escape our drug therapies — and it’s very easy for them.”

Treating glioblastoma: The plot thickens

The new findings indicate a need for combination therapies for glioblastoma that target all four tumor states at once. The researchers plan to try different combinations of gene editing approaches and drugs aimed at changing cell state. Such drugs could block molecular pathways that keep tumor cells in an immature state, or target the packaging of DNA into chromatin that determines what RNA is transcribed.

“Applying novel technologies to these vicious tumors give us an opportunity to understand what drives them at a whole new level that was unthinkable a few years ago,” said Filbin. “The time is ripe to take these findings and finally translate them into novel therapies.”