The activity of four transcription factors—proteins that regulate the expression of other genes—appears to distinguish the small proportion of glioblastoma cells responsible for the aggressiveness and treatment resistance of the deadly brain tumor. The findings by Harvard stem cell researchers at Massachusetts General Hospital (MGH), published in Cell, supports the importance of epigenetics—processes controlling whether or not genes are expressed—in cancer pathology and identify molecular circuits that may be targeted by new therapeutic approaches.

Several studies have used cell-surface markers—proteins found on the outer membranes of tumor cells—to identify glioblastoma stem cells; but the specific markers used have been controversial and cannot reflect molecular processes going on within tumor cells. The current study was designed to identify epigenetic factors that distinguish glioblastoma stem cells from more differentiated tumor cells and to suggest potential therapies targeting those factors.

In a series of experiments, the researchers first identified a set of 19 transcription factors that were expressed at significantly greater levels in cultured human glioblastoma stem cells capable of tumor propagation than in differentiated tumor cells. Testing each of these factors for their ability to return differentiated tumor cells to a stem-like state, identified a combination of four—POU3F2, SOX2, SALL2 and OLIG2—that was able to reprogram differentiated tumor cells back into glioblastoma stem cells, both in vitro and in an animal model.

The investigators then confirmed that these four factors and their corresponding regulatory elements—the DNA segments to which transcription factors bind—were active in two to seven percent of human glioblastoma cells, cells that also expressed a known stem cell marker. They also showed that inhibiting the action of an important regulatory protein complex that involves a known target gene of one of the core transcription factors—a gene active in stem-like glioblastoma cells but not differentiated cells—caused glioblastoma stem cells to lose their stem-like properties and die.

"This study brings us back to the fundamental idea that there are many reasons that cancer cells can be aggressive," explained senior author HSCI Affiliated Faculty member Bradley Bernstein, MD, PhD, of MGH Pathology and the MGH Cancer Center. "Just as normal cells with the same genome differentiate into many different cell types, a single tumor characterized by specific genetic mutations can contain many different types of cells—stem-like and more differentiated cells—with the difference being rooted in their epigenetic information. Identifying the drivers of these different cellular states in glioblastoma stem cells could offer us the best opportunity for treating what remains an extremely difficult-to-treat tumor."

"Understanding what drives these aggressive cells will give us insights into alternative ways of eliminating them and potentially changing the course of this very deadly tumor," said Mario Suvà, MD, PhD, of the MGH Department of Pathology and Center for Cancer Research, co-lead author of the Cell article."

The work was supported by grants from the Harvard Stem Cell Institute, the Howard Hughes Medical Institute, the Starr Cancer Consortium, the Burroughs Wellcome Fund, Oncosuisse and the Klarman Family Foundation.

Cited: Reconstructing and Reprogramming the Tumor-Propagating Potential of Glioblastoma Stem-like Cells. Cell. April 24, 2014

This story was provided by Massachusetts General Hospital.