University of Kentucky Center for Cancer and Metabolism (Pilot Project - Dr. Tianyan Gao)

Grants and Contracts Details

Description

Colorectal cancer is the second leading cause of cancer-related deaths in the United States. Approximately 136,000 new cases and 50,000 deaths are predicted for the year 2017; 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 adipose tissues in the tumor microenvironment (TME) as they first disseminate from their primary tumor site. However, how adipocytes support tumor growth and progression remains poorly understood. In our efforts to determine the functional importance of adipocytes in the TME, we uncovered a novel role of mitochondria in facilitating the metabolic crosstalk between adipocytes and colon cancer cells. To further elucidate the molecular mechanism, we discovered in our preliminary studies that uptake of free fatty acids triggers mitochondrial fragmentation in colon cancer cells by activating Drp1, a mediator of mitochondrial fission. Inhibition of Drp1-dependent mitochondrial fission eliminates the growth advantage provided by the adipocytes and disrupts cancer stem cell properties. The central hypothesis driving this proposal is that that Drp1-dependent mitochondrial dynamics plays a pivotal role in mediating the metabolic interaction between adipocytes and colon cancer cells. The following specific aims are proposed: 1) determine the functional importance of Drp1-dependent mitochondrial fission in mediating the tumor promoting effects of adipocytes; and 2) to delineate the molecular mechanism by which adipocytes enhance cancer stem cell properties. Results from this study will provide novel insights into the molecular mechanism underlying the tumor-promoting effect of adipocytes in colon cancer. The overall goal of our project fits the main focus of COBRE for Cancer and Metabolism. Our proposed studies will benefit greatly from the technologies and expertise available at the Metabolomics Core and the Imaging Core. The long-term goal for our study is to develop a mechanistic understanding of adipocyte-mediated regulation of cancer metabolism.
StatusFinished
Effective start/end date1/1/1912/31/19

Funding

  • National Institute of General Medical Sciences

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