Our research focus on understanding how relevant oncogenic events can transform neural stem cells (NSCs) and oligodendrocyte progenitor cells (OPCs) to generate distinct types of childhood and adult gliomas. 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. Recent publications confirm this relationship in genetically-engineered murine models (GEMM) of glioma. Other findings suggest that radiotherapy and changes in the tumor microenvironment can drive stemness and a proneural-mesenchymal transition in murine and human tumors.
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 if interstitial fluid pressure (IFP), myeloid cells, and hypoxia regulate tumor growth and relapse in glioma.
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. The vast majority of these tumors has R132H mutations in the IDH1 gene and is characterized by a hypermethylated phenotype and a better prognosis in patients. In high-grade glioblastoma (GBM), H3F3A (K27) and H3F3A (G34) tumors are expressed in young children and adolescent patients, respectively. Human GBMs expressing platelet-derived growth factor receptor A (PDGFRA) are diagnosed both in younger patients and adults. Interestingly, IDH1R132H and H3F3A (G34) human tumors are often localized to frontal cortex, a region enriched for OPC rather than NSCs. In contrast, H3F3A (K27) tumors are localized to the midline of the brain in thalamic and pons/medulla. Using GEMM of glioma, we are currently identifying the cell of origin and the first transforming steps that are observed in developing IDH1R132H, H3F3A mutant, and PDGFB driven tumors.
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. One major obstacle to study these TPCs in glioma is the absence of robust markers. We are developing density gradient protocols that will allow a more unbiased isolation of TPCs and further profiling of markers and signaling pathways using Affymetrix microRNA arrays. Candidate markers and drugable signaling pathways are then validated using patient biopsies and xenograft models. Other projects study the mechanisms regulating dormancy of TPCs and how miRNAs regulate stemness in glioma.
Influence of the tumor microenvironment on tumor growth and proneural-mesenchmal transition in glioblastoma
Increasing IFP during tumor progression is a major obstacle in glioma. High IFP reduces drug uptake in solid tumors. It is still unknown how high IFP regulate tumor growth in glioma. We have developed an in vivo model that allows us to accurately measure IFP in intracranial xenografts of human GBMs. We have identified a factor that effectively reduces IFP in GBMs, leading to massive apoptosis, depleted cell proliferation, and vascular reorganization. Another project studies if radiotherapy-induced changes in mechanosensing, infiltration of myeloid cells, and hypoxia contribute to tumor regrowth following radiotherapy in human xenografts.