Sarcoma Foundation of America Awards Research Grant to Dr. Michael Stacey for Study of Mitochondrial Epigenetic Processes in Chondrosarcoma
Michael Stacey
Sarcoma cancers including chondrosarcomas (CS), the most common form of bone cancer, can be extremely aggressive with high mortality rates and have been shown to harbor mutations in isocitrate-dehydrogenase-2 (IDH2) gene. When present, mutant IDH2 confer a cellular gain-of-function by converting alpha-ketoglutarate (αKG) produced by wild type IDH, to D-2-hydroxyglutarate (D2HG), a potent oncometabolite. This reaction occurs in the mitochondria as part of the Krebs cycle. D2HG plays a notable epigenetic role in the carcinogenic processes of cells by inducing DNA and RNA methylation. Of note is that αKG, a driver of DNA demethylation, is consumed by the mutant IDH2 enzyme to produce D2HG, a driver of DNA methylation, resulting in a hypermethylated phenotype in CS. In addition, and of particular significance to cancer progression/metastasis is the transfer of mitochondria between cancerous and normal cells, an important phenomenon in the tumor microenvironment, influencing doner and recipient cell physiology. Mitochondrial movement between cells in a cancer cells' microenvironment, more specifically in CS where mutant IDH2 induces D2HG, and methylated mitochondrial DNA (mtDNA) and RNA (mtRNA), may prime the tumor microenvironment to enhance tumor growth. Very little is known on how the accumulation of D2HG in the mitochondria may influence epigenetic events and gene expression of mitochondrial DNA, or how this affects mitochondrial metabolism in doner and recipient cells and are aims of the proposed study funded by the Sarcoma Foundation of America.
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