Grant: Project Grant

Glioblastoma (GBM) is the most common malignant brain tumor in adults. It is incurable, with average patient survival of about 14 months even with an aggressive therapeutic regimen consisting of maximal tumor resection, and concomitant chemotherapy and radiotherapy. One of the reasons for therapeutic failure is the complex functional heterogeneity in this brain tumor. In fact, not all cells are functionally identical in GBM, but a small population has properties reminiscent of normal stem cells, whereby they are uniquely responsible for tumor growth and recurrence. We call these specialized cells "cancer stem cells," or tumor-initiating cells. Whereas current treatments are relatively successful at targeting the other cells in this tumor, cancer stem cells have ways of evading current therapeutic intervention. We have recently shown that one feature that distinguishes cancer stem cells from the other cells in GBM is the way DNA is packaged. Cancer stem cells have regions of highly compacted DNA, which is caused by low levels of a protein that binds the DNA and relaxes its architecture. This protein is called H3.3. We have now identified macroH2A as another protein that may play a role in DNA packaging in cancer stem cells. We will characterize macroH2A, its function in orchestrating DNA packaging in cancer stem cells, and the way it affects the dynamics of tumor growth. These data will be used to rationally deploy a new generation of drugs that can affect DNA packaging. By changing the architecture of the DNA in cancer stem cells, we may be able to kill them or reprogram them into less lethal cell types that can be targeted by standard therapies. Eliminating cancer stem cells with novel techniques will be key to obliterating the ability of a tumor to grow and recur.