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An investigation of metabolic interactions between stromal cells and tumor cells

by
Brijesh Patel
M.S., 2009, Rutgers University

Thesis Advisor: Dr. Debabrata Banerjee, PhD

Graduate Program in Cell and Developmental Biology

UMDNJ Research Tower, 5th Floor Conference Room

Monday, June 10, 2013
1:00 p.m.


Abstract

Breast cancer development and metastatic progression is highly dependent on stromal support, particularly from carcinoma associated fibroblasts (CAFs). As a result of aerobic glycolysis, tumor cells produce and secrete copious amounts of lactate. Studies of metabolic cooperation in the brain and muscles indicate that lactate secreted by glycolytic cells is taken up by neighboring oxidative cells to support metabolic needs. We hypothesize that such metabolic coupling also exists between tumor cells and their stroma. In addition to extruding lactate as a byproduct of glycolysis, we suggest that tumor cells secrete the metabolite to recruit and subsequently exploit stromal cells to recycle lactate into utilizable metabolites, such as pyruvate, to fulfill metabolic demands of tumor cells. We show that MDA-MB-231 breast cancer cells (MDAs) secrete significantly higher levels of lactate under hypoxia, and that this monocarboxylate recruits mesenchymal stem cells (MSCs), the precursors of CAFs, towards tumor cells by activating signaling pathways to enhance migration. Lactate transport occurs via a family of monocarboxylate transporters (MCTs); MCT expression analysis in MDAs and CAFs indicate that a MDA-to-CAF lactate shuttle may mediate metabolic coupling between the two cell lines in a source-sink manner. Our investigation further revealed that that CAFs express the pro-oxidative isoform of pyruvate kinase and that expression of lactate dehydrogenase B and pyruvate dehydrogenase is induced upon lactate exposure. These data suggest that the lactate taken up by stromal cells is oxidatively metabolized. 13C-NMR analyses indicate that 13C-lactate is metabolized via the Krebs cycle and secreted from stromal cells as 13C-pyruvate, suggesting that the stroma may, in turn, provide this glycolytic intermediate to power metabolism in tumor cells. Indeed, treatment of MDAs with CAF-conditioned media increased pyruvate and glucose uptake in MDAs, and was concomitant with an increase in reactive oxygen species accumulation. Thus, CAFs may promote glycolysis in MDAs by provisioning pyruvate and by increasing intracellular ROS production. We find that inhibiting glucose uptake and monocarboxylate transport may antagonize reciprocal metabolic cooperation between tumors and their TME. A better understanding of the molecular mechanisms governing metabolic dependencies between the two niches will potentially identify new targets for therapeutic intervention.


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