Our research focus on understanding how oncogenic events can transform neural stem cells (NSCs) and oligodendrocyte progenitor cells (OPCs) into distinct types of childhood and adult gliomas. In addition, we have recently identified a previously unrecognized population of potential NSCs with tumorigenic capacity and regenerative potential. We are currently studying the regenerative potential of these cells during normal development and disease. In human gliomas, aggressive therapy leaves behind subpopulations of tumor cells displaying properties of NSCs or OPCs, suggesting a lineage-relationship between the cell of origin and therapy-resistant tumor cells. We and others have confirmed this relationship in genetically-engineered murine models (GEMM) of glioma. We use detailed knowledge about glial cells to identify the intrinsic and environmental components that impact glioma biology. We find that deregulation of NSC- and OPC-related microRNAs (miRNAs) regulate tumor biology in a glioma subtype-specific manner. Reintroduction of a single miRNA can turn glioblastoma (GBM) cells into neurons. We also study whether the cell of origin regulates response to ionizing radiation (IR) and the ability to regulate cell volume. Major goals: (i) Develop GEMM of glioma using relevant oncogenic events to identify the initial steps that transform NSCs and OPCs in a temporal and regional fashion. (ii) Identify drugable targets that drive stemness in glioma. (iii) Study the effect of IR and role of osmotic swelling on glioma biology.
Identification of a novel NSC population
We have established a team of collaborators to characterize the tumorigenic capacity potential of a novel NSC population. In addition, we study the regenerative potential using fate-mapping techniques during normal development and following traumatic brain injury (TBI). We also study cell genesis following stress, enriched environment, and exercise.
Development of IDH1R132H, H3F3A, and PDGF-driven mutant glioma models
Human gliomas displaying mutations in the isocitrate dehydrogenase 1/2 (IDH1/2) genes are diagnosed in young adults. In high-grade glioblastoma (GBM), H3F3A (K27) and H3F3A (G34) tumors are expressed in young children and adolescent patients, respectively. We are using retroviral (RCAS) transformation of cells expressing the TVA receptor to produce these tumors in mice.
Targeting stemness in glioblastoma
Pre-clinical experiments show that radiotherapy and treatment with temozolomide enrich for highly tumorigenic and stem-like tumor cells in human GBMs. We optimize IR regimens to better target these stem-like cells. Our laboratory use GEMMs and human GBM biopsies to study the mechanisms underlying treatment-resistance, including dormancy and epigenetic control of translation of genes. In particular, we identify small non-coding RNAs that regulate glioma biology.
Osmotic swelling as a therapeutic target in cancer
High pressure is a major obstacle for uptake in solid tumors, less is known how elevated interstitial fluid pressure impacts tumor biology. We find that high pressure drive tumor proliferation in solid cancers. In this NIH-supported project, we have identified a mechanism that blocks the ability of GBM cells to regulate cell volume, leading to massive apoptosis and reduced survival of xenografted mice. We currently test whether osmotic swelling regulates translational control of genes that drives GBM aggressiveness.