Date of Award
Mika B Jekabsons
Wayne L. Gray
Metastasis is responsible for the majority of cancer related deaths. In breast cancer the lungs and bones are the major sites for metastasis. Previous studies used the metastatic aggressive MDA-MB-231 breast cancer line to isolate sub-clones that preferentially invade the lungs (LM line) or bones (BoM line). While genes associated with the tissue specific metastasis have been identified, it is unknown if metabolic adaptations contribute to the growth of the LM and BoM lines in their respective organs. The goal of this study was to test the hypothesis that the LM and BoM lines exhibit differences in glucose and glutamine metabolism from their parent MDA-MB-231 breast cancer line. Such differences would support the broader concept of metabolic plasticity as an important component of cancer metastasis. We used 13C- metabolic flux analysis with 5-13C glutamine as the labeled substrate. The rates of glucose uptake, glutamine uptake, respiration, and lactate production were measured, together with 13C enrichment of lactate. In parallel, the fraction of glutamine and glucose used for fatty acid synthesis was assessed with the fatty acid synthase inhibitor C75. The measured fluxes were used to determine fluxes through glycolysis, the pentose phosphate pathway, the tricarboxylic acid (TCA) cycle, malic enzyme, and to fatty acids. The LM and BoM cells exhibited significant metabolic differences from each other and the MDA231 parent line, this supports our hypothesis and is consistent with such changes contributing to organ-specific growth of these lines. Specifically, the LM and BoM lines have significantly lower mitochondrial TCA cycle and respiratory chain activities. The LM cells have a significantly higher malic enzyme flux, which together with restricted mitochondrial activity, are proposed to reduce oxidative stress in the high oxygen environment of the lungs. The BoM cells that metastasize to bones consume significantly less glutamine and have low mitochondrial activity suggesting they rely more heavily on aerobic glycolysis for ATP synthesis in the oxygen-limited bone environment. These metabolic adaptations suggest that organ specific metabolic difference may be a new way to potentially target these cells through development of drugs.
Merrell, Mollie, "Breast Cancer Sub-Clones that Metastasize to Lung and Bone Exhibit Different Metabolic Preferences" (2020). Honors Theses. 1412.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.