Undergraduate university: University of Notre Dame
Brain tumors are the most common type of solid tumor and the second most common cancer in children. They cover a diverse spectrum embodying a range of pathological and molecular characteristics. Gliomas are a specific type of brain cancer that are the greatest cause of cancer-related death in patients under 19 years old. Recent advancements in genomic and epigenomic regulation have elucidated a stark distinction between adult and pediatric brain cancers. Incorporating these tumors’ molecular, epigenetic, and genetic modifications has revealed distinct clinicopathological and biological subgroups. Two of these subgroups are defined by driver mutations in the H3.3 variant protein and IDH1 protein. H3.3G34R-driven gliomas are typically characterized as high-grade gliomas and originate in interneuron progenitor cells. The H3.3G34R mutation causes widescale epigenetic dysregulation, preventing terminal differentiation of the progenitor cell and allowing the cell to maintain stem cell-like characteristics. Over successive cell divisions, the cell co-opts a gain of function mutation in PDGFRA and loss of function mutations in p53 and ATRX, which push tumorigenesis. IDH1R132H-driven tumors are classified as low-grade gliomas, and glial progenitor cells have been identified as the cell of origin for tumorigenesis. The IDH1R132H gain of function mutation converts a-KG to D-2HG, an oncometabolite that leads to epigenetic dysregulation. Like the H3.3G34R mutation, IDH1R132H results in a block of terminal differentiation and maintenance of self-renewal capabilities. Over time, the cell acquires similar co-occurring mutations as H3.3G34R-driven gliomas and results in tumorigenesis. The need for continual therapeutic development is dire for both cancers. Proper models are needed to understand these tumors’ biology and develop targetable therapeutics. I hypothesized that transfecting mice neural stem cells with the mutations seen in the human cancers would lead to the creation of faithful models of the cancers, with an enhanced proliferative potential in the cells and a differentiation/stem marker signature that replicates the human counterpart. My team and I created in vitro and ex vivo tumor-derived H3.3G34R and IDH1R132H-driven gliomas. My analysis showed that the models recapitulate the same stem/differentiated marker signature and proliferative behavior seen in their human counterparts. Future studies will evaluate the efficacy of therapeutically targeting the driver and partner mutations with the models.