Through single-cell RNA sequencing of low-grade oligodendrogliomas, researchers have identified a cell population featuring a gene expression signature similar to those of neural stem and progenitor cells. These cancer stem cells have enriched proliferative potential and may be responsible for fueling the growth of this glioma subtype.

Cancer stem cells may drive the development of oligodendroglioma, an incurable brain tumor characterized by IDH1 or IDH2 mutations, a new study reveals (Nature 2016;539:309–13).

Researchers led by Mario Suvà, MD, PhD, of Massachusetts General Hospital in Boston, and Aviv Regev, PhD, of the Broad Institute in Cambridge, MA, weren't trying to track down cancer stem cells when they began their study. Instead, Suvà says, “we wanted to understand the composition of oligodendrogliomas early in their development in an unbiased way.”

The researchers used RNA sequencing to profile individual cells from six untreated low-grade tumors, analyzing a total of 4,347 cells. Gene expression patterns indicated that the cells fell into three categories. One group had high levels of oligodendrocyte markers such as OLIG1 and OMG. Expression of these markers was low in the second group, which instead featured high levels of astrocyte markers such as APOE and ALDOC. Overall, the differentiation paths of these two groups of cancer cells resembled lineage maturation in oligodendrocytes and astrocytes.

The third group caught the researchers' attention. These cells were undifferentiated and expressed transcription factors required by stem cells, such as SOX4 and SOX2, suggesting that they could be cancer stem or progenitor cells. Supporting that inference, the gene expression patterns in these cells were very similar to those of mouse neural stem cells and human neural progenitor cells. Within each of the six tumors, the scientists pinpointed a small proportion (1.5% to 8%) of actively proliferating cells, which they determined mostly belonged to this third category of stem/progenitor cells.

“We think that we've identified a cancer stem cell population that is responsible for fueling the growth of these tumors,” Suvà says. Other studies have discovered likely cancer stem cells in glioblastoma, he says, but whether they occur in low-grade, IDH1- or IDH2-mutant gliomas has been unclear.

When the researchers used copy-number variation and point mutation analyses to sort their cells into subclones, they found that many subclones contained cells from all three categories identified through RNA sequencing. These results imply that the identity of oligodendroglioma cells is not primarily determined by genetic events, but rather by nongenetic developmental programs.

Suvà acknowledges one caveat of the study: Because low-grade oligodendroglioma xenografts don't grow in mice, the researchers couldn't functionally validate the stem/progenitor cell category they found. However, he thinks it might be possible to curb oligodendroglioma growth by targeting the stem/progenitor cells with immunotherapies, such as CAR T cells engineered to home in on markers on the stem cells.

The single-cell RNA-sequencing technique that Suvà's team used provides strong evidence that cells in this category are indeed cancer stem cells, says Justin Lathia, PhD, of the Cleveland Clinic Lerner College of Medicine in Ohio, who wasn't connected to the study. “What's really exciting is to see the stem cell signature within this tumor type.” Now, he adds, the researchers will need to determine how this population responds to treatment and also figure out individual cells' role in resistance. –Mitch Leslie

For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.