The breast microenvironment plays an important role in cancer progression through the interaction between epithelial and stromal cells. Cancer stromal cells may function as regulatory cells to provide high-energy mitochondrial fuels through ketogenesis, and promote reverse Warburg effect in tumor cells that converts ketone bodies to acetyl-CoA for the TCA cycle. Thus, the coupling of ketogenesis and ketone body re-utilization is important to drive oxidative phosphorylation to fuel anabolic tumor growth under nutrients starvation and hypoxia conditions. Based on our preliminary findings of heterogeneous expression of mitochondrial HMG-CoA synthase (HMGCS2), the rate-limiting enzyme of ketogenic pathway, in breast cancer tissues and cell lines, we hypothesize that ketone bodies can be generated in stromal cells and in HMGCS2+ tumor cells, which in turn promotes tumor growth by re-utilization of ketone bodies in HMGCS2- tumor cells. We will set up a co-culture system of tumor cells and fibroblasts to determine whether HMGCS2-mediated ketogenesis promotes tumor cell proliferation and invasion, and then further explore signaling pathways involved in stromal-epithelial interaction by suppressing ketogenesis using HMGCS2-siRNA or metabolism-inhibitory compounds. We believe this study will lead to finding a new way to cut lipid metabolism-derived nutrients and energy supplies and suppress tumor growth.
|Effective start/end date
|9/1/14 → 8/31/16
- Northwestern Memorial Hospital (LSCRFGI)
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