Date of Award

8-2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Bioengineering

Committee Member

Sarah W Harcum, Committee Chair

Committee Member

Kim Paul

Committee Member

Ying Mei

Committee Member

Agneta Simionescu

Abstract

Proliferative cells, including many types of cancer and pluripotent stem cells, rely primarily on glycolysis and lactate metabolism for energy, regardless of oxygen availability. This metabolic phenotype – referred to as the Warburg effect – results in wasteful lactate accumulation. Although cancer cells and pluripotent stem cells share this central metabolic characteristic, the sensitivities of each of these cell types to lactate stress appear contradictory. While lactate accumulation is thought to adversely impact pluripotent stem cell proliferation and differentiation capacities, cancer cells have been shown to possess bioenergetic plasticity to utilize lactate catabolism for fuel. As a result, lactate buildup within the hypoxic tumor microenvironment has been hypothesized to promote cancer progression and malignancy, in part by selecting for cancer populations capable of catabolizing lactate. Moreover, lactate has been shown to promote "stemness" gene expression in cancer, suggesting that lactate plays a functional role in regulating pluripotency gene expression. However, an incomplete understanding of the impact of lactate on intracellular metabolism for proliferative cells remains. In this work, 13C-metabolic flux analysis was used to quantify the intracellular metabolic responses of breast cancer cells and induced pluripotent stem cells (iPSCs) to high extracellular lactate; in particular, to determine the role of lactate as a metabolic substrate. In this research, it was demonstrated that both iPSCs and breast cancer cells employ dual consumption of glucose and lactate to support growth. In addition, this is the first study to determine and quantify intracellular contribution of lactate in proliferative iPSC metabolism. These results provide insight into the metabolic flexibility of highly proliferative cells with respect to lactate metabolism and suggest that, much like many types of cancer cells, iPSCs possess the capacity to metabolize lactate to promote exponential growth and maintain pluripotency.

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