Date of Award
Mika B Jekabsons
Malignant breast cancers exhibit preferential metastasis to bone and lung (1). While changes in gene expression in lung-specific (LM) and bone-specific metastasis (BoM) lines derived from the MDA-MB-231 breast cancer line have been identified, few metabolic genes are differentially expressed; thus it is unknown if tissue-specific metabolic reprogramming occurs. Two hallmarks of cancer cells are an altered metabolic phenotype characterized by enhanced conversion of glucose to lactate in spite of adequate oxygen availability for complete mitochondrial oxidation of this substrate (referred to as aerobic glycolysis or the Warburg effect) and a greater dependence on glutamine. These changes in primary tumor metabolism are crucial for cancer cell metastasis by increasing the supply of glycolytic and tricarboxylic acid (TCA) cycle intermediates that are necessary for de novo biosynthetic pathways. I hypothesize that the LM and BoM lines exhibit metabolic reprogramming to allow for proliferation in the lung and bone microenvironments, respectively. The rates of glucose consumption, mitochondrial respiration, and lactate production were determined for MDA-MB-231, LM, BoM, and the less aggressive T47D lines given either glucose or glucose and glutamine as the exogenous substrates. Aerobic glycolysis for the BoM and LM lines, was greater than the MDA231 and T47D lines. Respiration rate was significantly lower in the BoM and LM lines. Glutamine consumption normalized to glucose consumption was significantly lower for BoM cells, suggesting this line has a lower preference for glutamine. Glutamine had significant main effects on glucose uptake, lactate production, and a near significant effect on aerobic glycolysis; the effect of glutamine on mitochondrial respiration was cell line dependent, as this substrate tended to reduce T47D and MDA231 respiration while increasing it in LM cells. These data indicate that the LM and BoM sub-clones have different metabolic phenotypes than the parent MDA-MB-231 cells and the extent of the differences is affected by glutamine. Further, the LM and BoM phenotypes differ from each other given their responses to exogenous glutamine. Successful growth of metastatic cells from a primary tumor in secondary organs such as lung and bone may thus require metabolic plasticity characterized by higher aerobic glycolysis and lower mitochondrial activity.
Skubiz, Anna G., "glucose metabolism of breast cancer sub-clones that preferentially metastasize to the lungs and bone" (2020). Honors Theses. 1337.
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