Therapeutic epigenetic reprogramming of brain cancer stem cells using microRNAs
Glioblastoma is a devastating form of brain cancer with no known cure. The existence of different types of cancer cells with diverse biological properties in the same glioblastoma tumor significantly contributes to the treatment failures observed in patients. Within glioblastoma tumors, a therapy-resistant population of cancer cells called cancer stem cells (CSCs) are thought to be responsible for treatment failures and disease recurrence, necessitating the discovery of strategies to confront this challenging cell pool. The malignant cell state of CSCs is dynamic and defined by a unique epigenetic profile. Recently, specific microRNAs were demonstrated to instruct human fibroblasts to become neurons through an epigenetic process called direct reprogramming. These results raise the exciting possibility that microRNAdirected epigenetic reprogramming might be harnessed to convert the malignant cell state of CSCs into a non-tumorigenic, neuron-like state. In preliminary data, we have found that expression of specific microRNAs in patient tumor-derived glioblastoma CSCs causes cells to stop dividing and dramatically decreases overall cell number. The major goals of this proposal are to demonstrate proof-of-concept, preclinical evidence for this innovative strategy using an animal model of glioblastoma with high fidelity to the human clinical scenario and also to identify the key epigenetic changes triggered by these therapeutic microRNAs, which will provide the foundational knowledge for a desired chromatin state for CSCs. The long-term goal of this proposal is to development novel strategies against glioblastoma by utilizing therapeutic reprogramming. Finally, these experiments will reveal fundamental insights into the epigenetic mechanisms underlying direct reprogramming into neurons, with ramifications for our understanding of nervous system development.