Abstract/Description/Artist Statement
Chondrosarcoma (CS) are common bone cancers that produce cartilaginous tumors and are extremely refractive to chemo-and-radiation therapies, leaving very limited treatment options. They contain mutations in the isocitrate dehydrogenase genes, IDH1 or IDH2. Either IDH1 or IDH2 mutations are present in individual tumors, but not both. They both convert alphaketoglutarate (αKG) into the potent oncometabolite D-2-hydroxyglutarate (D2HG). D2HG can be transported from the tumors to cells of the tumor microenvironment (TME) where it can alter metabolic and epigenetic profiles in recipient cells. The process of α-KG to D2HG conversion occurs in the cytoplasm of IDH1 mutant cells, and in the mitochondria in IDH2 mutants. Our preliminary data shows that mitochondrial exchange occurs between an IDH2 mutant CS cell line cocultured in 2D with a normal immune lymphoblastoid cell line (LCL) and is accompanied by metabolic enhancement in CS cells but not LCLs. Our objective now is to investigate mitochondrial transfer in a 3D collagen gel, chosen to mimic the microenvironment of cartilage forming chondrosarcomas. We hypothesize that mitochondrial exchange will enhance the function and vitality of IDH2 mutant chondrosarcomas by increasing ATP production. As a treatment option, reversal of tumor derived ATP production may be beneficial to a patient, and the objective of this work is to achieve reversal and propose a novel therapeutic approach. We will address the hypothesis by growing IDH2 mutant chondrosarcoma with the monocytic cell line HL60 in a collagen type 1 gel and measure increased ATP production in CS cells following receipt of mitochondria from HL60 cells. To reverse ATP production, we propose a mechanism to increase local reactive oxygen species (ROS) production. Increased ROS production in the matrix will damage mitochondrial physical integrity, mitochondrial DNA, and permeability of the inner mitochondrial membrane. This oxidative stress alters mitochondrial function and results in inhibited ATP production. We propose to increase ROS and decrease ATP production by exposing a tumor organoid to blue light. Blue light frequency, in the range of 400- 470 nm, has been shown to induce ROS production by causing excitability in mitochondrial chromatophores within the electron transport chain (ETC). The excited chromophores secrete electrons that subsequently cause an increased production of ROS like superoxide anions. At the end of this project, we expect to have shown that blue light decreases tumor cell survival through mechanisms including ROS and ATP production.
Faculty Advisor/Mentor
Mike Stacey
Faculty Advisor/Mentor Email
Mstacey@odu.edu
Faculty Advisor/Mentor Department
Bioelectrics
College/School Affiliation
Other
Student Level Group
Undergraduate
Presentation Type
Poster
Mitochondrial Transfer and Induced ROS as a Therapeutic Strategy in IDH2-Mutant Chondrosarcoma
Chondrosarcoma (CS) are common bone cancers that produce cartilaginous tumors and are extremely refractive to chemo-and-radiation therapies, leaving very limited treatment options. They contain mutations in the isocitrate dehydrogenase genes, IDH1 or IDH2. Either IDH1 or IDH2 mutations are present in individual tumors, but not both. They both convert alphaketoglutarate (αKG) into the potent oncometabolite D-2-hydroxyglutarate (D2HG). D2HG can be transported from the tumors to cells of the tumor microenvironment (TME) where it can alter metabolic and epigenetic profiles in recipient cells. The process of α-KG to D2HG conversion occurs in the cytoplasm of IDH1 mutant cells, and in the mitochondria in IDH2 mutants. Our preliminary data shows that mitochondrial exchange occurs between an IDH2 mutant CS cell line cocultured in 2D with a normal immune lymphoblastoid cell line (LCL) and is accompanied by metabolic enhancement in CS cells but not LCLs. Our objective now is to investigate mitochondrial transfer in a 3D collagen gel, chosen to mimic the microenvironment of cartilage forming chondrosarcomas. We hypothesize that mitochondrial exchange will enhance the function and vitality of IDH2 mutant chondrosarcomas by increasing ATP production. As a treatment option, reversal of tumor derived ATP production may be beneficial to a patient, and the objective of this work is to achieve reversal and propose a novel therapeutic approach. We will address the hypothesis by growing IDH2 mutant chondrosarcoma with the monocytic cell line HL60 in a collagen type 1 gel and measure increased ATP production in CS cells following receipt of mitochondria from HL60 cells. To reverse ATP production, we propose a mechanism to increase local reactive oxygen species (ROS) production. Increased ROS production in the matrix will damage mitochondrial physical integrity, mitochondrial DNA, and permeability of the inner mitochondrial membrane. This oxidative stress alters mitochondrial function and results in inhibited ATP production. We propose to increase ROS and decrease ATP production by exposing a tumor organoid to blue light. Blue light frequency, in the range of 400- 470 nm, has been shown to induce ROS production by causing excitability in mitochondrial chromatophores within the electron transport chain (ETC). The excited chromophores secrete electrons that subsequently cause an increased production of ROS like superoxide anions. At the end of this project, we expect to have shown that blue light decreases tumor cell survival through mechanisms including ROS and ATP production.