Exploring the Role of Drp1 in Colorectal Cancer

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Abstract - Exploring the Role of Drp1 in Colorectal Cancer. Colorectal cancer is the second leading cause of cancer-related deaths in the United States. Approximately 150,000 new cases and 50,000 deaths are predicted for the year 2020. Emerging research suggests that the dysregulation of mitochondrial fitness due to an imbalance in mitochondrial dynamics can lead to metabolic reprogramming in various cancer types. A number of epidemiological studies indicate that obesity is as a major risk factor for several types of cancer including colorectal cancer. Our group and others have shown that increased uptake of fatty acids promotes the development and progression of difference cancers by altering metabolic pathways to favor mitochondrial fatty acid oxidation. However, the molecular mechanisms by which fatty acid consumption influences mitochondrial fitness to promote tumor cell survival and progression is poorly understood. In this proposed study, I plan to investigate the signaling crosstalk between mitochondrial dynamics and fatty acid metabolism in colorectal cancer. In my preliminary experiments, I discovered that fatty acid uptake promotes mitochondrial fragmentation by activating Drp1, a small GTPase required for mitochondrial fission, by increasing the phosphorylation at the S616 site and its interaction with mitochondria. Importantly, silencing Drp1 inhibits cancer stem cell functions by attenuating Wnt signaling in colon cancer cells. The central hypothesis is that Drp1-dependent mitochondrial fission is required for fatty acids to promote tumor progression in colon cancer. Specifically, I will determine how fatty acid uptake alters Drp1 activity and how mitochondrial dynamics augments cancer stem cell functions to drive tumorigenesis in vivo. The following specific aims are proposed: 1) to delineate the molecular mechanism by which fatty acid uptake enhances Drp1 activity; 2) to determine the functional importance of Drp1 in promoting CSC functions in colorectal cancer; and 3) to define the role of Drp1 in regulating tumorigenesis using in vivo colon cancer models. Results from this study will provide novel insights into the role of mitochondrial dynamics in connecting cellular metabolic pathways with cancer stem cell signaling. Dr. Gao has extensive experience in studying the regulation of signaling pathways and mitochondrial metabolism in colorectal cancer. I will also benefit from additional expertise provided by my committee members and state- of-the-art facilities of the Markey Cancer Center at the University of Kentucky. A comprehensive training plan has been developed to fit my research background and career goals. Based on my strong preliminary data, with my mentor’s knowledge and training, and the excellent research environment at the Department of Molecular and Cellular Biochemistry and the Markey Cancer Center I am confident that this project will be successful. Ultimately, this study will help develop personalized treatment options by targeting mitochondrial dynamics to eradicate cancer stem cells.