CCL5-CCR5 Interactions in Breast Cancer Regulate Cell Metabolism

Chemokines are chemotactic cytokines that recruit and activate leukocytes. It is now apparent that they also participate actively in the neoplastic process in cancer. This thesis describes the importance of the activation of CCR5 by the inflammatory chemokine CCL5/RANTES in the context of cancer metabolism. Specifically, CCL5-CCR5 interactions promote anabolic metabolism in breast cancer cells and enhance cell proliferation. CCL5 activation of CCR5 invokes the mTOR/AKT signaling pathway and, within minutes, induces phosphorylation of downstream substrates, including GSK-3β and 4E-BP1. Using a panel of CCR5-expressing breast cancer cells, we show that CCL5 also increases surface GLUT-1 expression, glucose uptake, ATP production and the glycolytic capacity of these tumor cells. Using metabolomics, we demonstrate that the metabolic signature of primary mouse mammary tumor cells that express CCR5 is altered by CCL5 treatment and reflects enhanced anabolic metabolism, resulting in the accumulation of biosynthetic precursors. Concomitant with enhanced anabolic metabolism, we show that CCL5 increases the proliferation and invasive capacity of breast cancer cells. Moreover, in an immune-deficient tumor transplant mouse model, we identify a direct correlation between reduced tumor proliferation and decreased metabolic activity, specifically associated with the absence of CCR5 expression by tumor cells. Using Matrix-Assisted Laser Desorption/Ionization Fourier Transform Ion Cyclotron Resonance Mass Spectrometry imaging, we provide evidence that the rapid early growth of CCR5+/+ triple negative breast cancer cells in vivo is attributable to increased levels of glycolytic intermediates required for anabolic processes, in contrast to the slower growth rate of their corresponding CCR5-/- cells, that exhibit reduced glycolytic metabolism. Collectively, these studies suggest that CCL5-CCR5 interactions in the tumor microenvironment modulate metabolic events during tumor onset to promote tumorigenesis.Ph.D