Epigenetic circuits reveal glioblastoma stem cells, potential therapy

A small group of proteins called transcription factors that regulate genetic expression tip off the mother cells of very aggressive and therapy-resistant brain cancer, according to Massachusetts General Hospital (MGH) research announced by the institution yesterday.

Investigators including Mario Suva, MD, PhD, from the MGH department of pathology and center for cancer research, identified the molecular circuits that could be ideal targets for novel therapies manipulating the on-off switches of glioblastoma stem cells. The research is scheduled to be published in Cell later this month.

"We have identified a code of 'molecular switches' that control a very aggressive subpopulation of brain cancer cells, so-called glioblastoma stem cells," said Suva, co-author of the study, in a statement from MGH. "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."

A number of research studies have focused on protein biomarkers on the cell’s surface to pinpoint glioblastoma stem cells, but they have all fallen short of showing what is really going on at the molecular level. This study clearly outlines the domino effect that not only differentiates glioblastoma stem cells from other tumor cells, but the epigenetic processes that lead to the development of glioblastoma. Researchers were able to test four specific factors that shift differentiated tumor cells back into a stem cell state. These genetic factors were identified as SALL2, OLIG2, POU3F2 and SOX2.  

"This study brings us back to the fundamental idea that there are many reasons that cancer cells can be aggressive," said co-author Bradley Bernstein, MD, PhD, from the MGH Cancer Center and department of pathology. "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."

Researchers highlighted that the segments of DNA that these transcription factors bind with are present in anywhere from 2 percent to 7 percent of glioblastoma cells in humans. Inhibiting a protein complex involved in this transcription process has been shown to strip glioblastoma cells of their stem shape, which tends to kill them off. This could be the key to novel therapies in the future.