Our laboratory studies the regulation of stem cell function in malignant brain tumors. By definition, stem cells possess two fundamental properties: self-renewal, the ability to preserve stemness; and multi-potency, the ability to differentiate to different types of progeny. Our group investigates the molecular mechanisms that govern self-renewal and differentiation potential of cancer stem cells in brain tumors, such as gliomas.

A major project in our laboratory aims to identify distinct classes of cancer stem cells in glioblastoma. Glioblastoma is an aggressive form of brain cancer, in which stem-like cells termed glioblastoma stem cells (GSCs) can recapitulate the entire tumor, while remaining resistant to chemotherapy and radiation. To study GSC biology, we obtain primary human GBM tissue from operative specimens, culture it and inject it into the mouse brain to generate tumor xenografts. Using genetic techniques and lentiviral vectors, we interrogate distinct types of human GSCs for the lineages that they generate in vitro and in vivo, molecular markers, metabolic profile and response to treatment. As a result of this effort, we recently identified an adhesion G protein-coupled receptor, GPR133, which is required for glioblastoma growth. We are currently elucidating basic mechanisms of action of GPR133, but also developing it translationally as a novel therapeutic target.

An additional area of research in the laboratory focuses on understanding the early steps of gliomagenesis. Over the past few years, brain tumor sequencing has indicated that neomorphic mutations in the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) are highly prevalent in low-grade glioma, a slow-growing precursor to glioblastoma. We recently used a human neural stem cell platform to show that tumor initiation by mutant IDH1 is mediated by chromatin conformation changes, which result in reorganization of transcription factor networks that regulate differentiation. We are currently pursuing genetic, biochemical and pharmacologic approaches to elucidate epigenetic changes during glioma initiation and identify novel dependencies of tumor cells.

1. Heterogeneity in the cancer stem cell population in glioblastoma.

2. Modeling the origins of glioma with human embryonic stem cells.

3. The role of GPR133 in glioblastoma biology.