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Description
Gliomas and glioblastomas are a type of tumor that originates in the brain. Mutations in the IDH1 gene, which encodes for the enzyme isocitrate dehydrogenase 1, drive >70% of lower grade gliomas and secondary glioblastomas. Normally, IDH1 catalyzes the conversion of isocitrate to alpha-ketoglutarate (aKG) in an NADP+ -dependent reaction. aKG is necessary to maintain the citric acid cycle and thus ultimately the production of ATP. IDH1 wild-type gliomas are aggressive and quickly progress, with generally poor overall survival. It has been shown that gliomas with a point mutation in the IDH1 gene, specifically the substitution of arginine with histidine at residue 132, have improved prognosis compared to wild-type IDH1 gliomas. The underlying mechanism of how this mutation confers longer survival is not yet completely understood. These mutations in IDH1 confer a neomorphic activity, the NADPH- dependent conversion of aKG to D-2-hydroxyglutarate, an oncometabolite that can inhibit collagen maturation enzymes. In this project we investigate how expression of wild-type and mutant IDH1 affects migratory patterns and proliferation rates of the cell in response to the substrate stiffness. We fabricated a series of collagen-coated polyacrylamide hydrogel substrates of variable stiffnesses. Wound-healing assays were performed on uncoated and collagen-coated polystyrene surfaces to study the migration rates of parental U87MG and R132H mutant cells. Proliferation rate assays were performed by counting the number of cells in a given area over a period of 72 h. We hypothesized that cells with the R132H IDH1 mutation migrate and proliferate slower than that of the parental U87MG and wild-type IDH1within softer brain tissue mimicking environments. By quantifying the effects of substrate stiffness on cell fate, we can elucidate new genotype-phenotype mechanisms driving aggressive glioma progression.
