Metabolic Reprogramming Following Mitochondrial Transfer Between IDH2 Mutant Chondrosarcoma Cells and a Normal B-Cell Line

Chondrosarcoma, glioblastoma, acute myeloid leukemia, chronic lymphocytic leukemia, and cholangiocarcinoma, cancers all contain mutations in the gene isocitrate dehydrogenase 2 (IDH2). The mutant IDH2 enzyme metabolizes alpha-ketoglutarate (αKG) into the potent oncometabolite D-2-hydroxyglutarate (D2HG) in the mitochondria of these cancers. Mitochondrial-mediated transfer between cancer and recipient cells is a significant event that impacts the metabolism of both cell types. The presence of intercellular nanotubular structures between IDH2 mutant chondrosarcoma cells motivated investigation into mitochondria-mediated physiological alterations resulting from mitochondrial transfer to immune cells. Mitochondrial transfer is a two-way process, and we hypothesized that mitochondria derived from IDH2-mutant chondrosarcoma cells co-cultured with normal cells occurred between cells through tunneling nanotubes. We further hypothesize that disruption of the actin cytoskeleton will inhibit this transfer. Our objectives were 1). Quantify the exchange and directionality of mitochondria via nanotubes between IDH2 mutant cells and wild-type cells and modulate transfer via cytoskeletal inhibitors, and 2) measure metabolic changes in cells following transfer. The experimental data acquired here increased our understanding of the molecular mechanisms behind the progression of IDH2 cancers as they interact with normal cells in the tumor microenvironment, advancing our understanding of intercellular communication in cancer biology.