Study of Mitochondrial OXPHOS in Colon Cancer Stem Cells

Abstract Colorectal cancer is the second leading cause of cancer-related deaths in the United States. Approximately 145,000 new cases and 51,000 deaths are predicted for the year 2019; and the mortality is predominantly due to the development of disseminated disease and resistant to conventional chemotherapy. A better understanding of molecular mechanisms leading to chemoresistance and recurrence is urgently needed in order to improve the overall patient survival. Altered metabolism has been widely recognized as a common hallmark of cancer. The best-characterized metabolic perturbation in cancer cells is an increased utilization of glucose (i.e., the Warburg effect). However, the role of mitochondrial oxidative phosphorylation (OXPHOS) in regulating tumor initiation and progression remains poorly understood. The overall objective of this study is to elucidate the molecular mechanisms by which mitochondria regulate cancer stem cell (CSC) functions and tumorigenesis in colon cancer. In our efforts to investigate the functional importance of mitochondrial OXPHOS in colon cancer, we disrupted the mitochondrial function by silencing QPc (Uqcrq), a structural subunit in mitochondrial complex III. Our preliminary results demonstrated that disruption of mitochondrial complex III resulted in a significant decrease in Wnt/β-catenin signaling and CSC properties. In addition, we found that mitochondria-derived reactive oxygen species (ROS) functioned as signaling molecules to fine-tune the transcriptional activity of b- catenin and the amplitude of Wnt signaling. The central hypothesis driving this proposal is that mitochondrial OXPHOS plays an important role in promoting Wnt/b-catenin signaling to support CSCs and tumorigenesis. We will investigate the functional importance of mitochondrial OXPHOS in sustaining CSCs and the signaling crosstalk between FOXO-driven oxidative stress responses and the Wnt pathway. The following specific aims are proposed: 1) to delineate the molecular mechanisms by which mitochondria regulate CSCs; and 2) to define the role of mitochondrial OXPHOS in promoting tumorigenesis in vivo. We will utilize a new QPcf/f mouse model to interrogate mitochondrial OXPHOS-dependent regulation of normal and cancer stem cells. Our proposed study centers on a novel hypothesis that the mitochondrial OXPHOS drives Wnt signaling to promote CSC functions in colon cancer. Knowledge gained from our study will help to develop new therapeutic options that target metabolic vulnerabilities of CSCs. The overall goal of our project fits the main focus of the Center for Cancer and Metabolism. Our proposed studies will benefit greatly from the technologies and expertise available at the Metabolomics Core and the Imaging Core. We are actively pursuing NIH funding to support this project. The pilot funding here will provide the necessary resource for generating additional preliminary data to strengthen future R01 applications.