NRSA Fellowship for Hasani: Exploring the Role of Drp1 in Colorectal Cancer

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; this mortality is predominantly due to the development of disseminated advanced disease. A better understanding of the metastatic tumor and its microenvironment is urgently needed in order to improve the overall survival of colorectal cancer patients. Colon tumors grow in an adipose tissue-enriched microenvironment. Metastatic colon cancer cells often encounter fatty acid-releasing adipose tissues in the tumor microenvironment as they first disseminate from their primary tumor site. However, how excreted fatty acids support tumor growth and progression remains poorly understood. The overall objective here is to develop a mechanistic understanding of mitochondria-dependent retrograde signaling in mediating the communication between fatty acids and colon cancer cells. In our efforts to determine the tumor-promoting effect of fatty acids, we uncovered a novel role of mitochondria in facilitating the metabolic crosstalk between adipocytes and colon cancer cells. To further elucidate the molecular mechanism by which adipocytes modulate colon cancer metabolism, we discovered in our preliminary studies that uptake of fatty acids triggers mitochondrial fragmentation in cancer cells by activating Drp1, a key regulator of mitochondrial fission. Inhibition of Drp1-dependent mitochondrial fission reduces mitochondrial fatty acid oxidation, eliminates the growth advantage provided by fatty acids and disrupts cancer stem cell properties in colon cancer cells. The central hypothesis driving this proposal is that that Drp1-dependent regulation of mitochondrial dynamics plays a pivotal role in mediating the metabolic interaction between fatty acids and colon cancer cells. We are particularly interested in determining the functional contribution of mitochondrial dynamics in promoting tumorigenesis and the molecular mechanism by which fatty acids enhance cancer stem cell properties. 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 a novel insight into the role of mitochondrial dynamics in enabling fatty acid- cancer cell interaction to support tumor progression. To ensure the success of this study, we have built a highly collaborative team that has the requisite expertise in cancer signaling and mitochondrial metabolism. Utilizing innovative model systems and state-of-the-art technologies, we are in a unique position to significantly advance our understanding of mitochondria-nucleus communication in cancer in cancer. Ultimately, our studies will help to develop personalized treatment options by targeting fatty acid-cancer cell interaction.