Defining Roles for Mitochondrial Polymorphisms in Mediating Immune Cell Trafficking, Differentiation, and Metastasis
Abstract
Scientific Objective and Rationale: This fellowship project seeks to define the role of the mitochondria in regulating metastatic breast cancer susceptibility. Mitochondria are like the factories of the cell. They produce the energy necessary for the cell to function. Since it is inherited almost exclusively from the mother, the mitochondria also define lineage and race. For instance, companies like Ancestry.com or 23andMe use mitochondrial DNA (mtDNA) to trace our ancestry through our maternal lineage. Our preliminary data, along with data from similar studies, have demonstrated mtDNA regulates cancer’s tendency to grow and spread to other parts of the body (metastasize). Although mtDNA is unlikely to be the sole contributing factor, these data do provide evidence that a cancer’s likelihood (susceptibility) to metastasize has an inherited element. We have demonstrated differences in mtDNA are relevant factors in cancer cells and in the tumor’s surrounding microenvironment. These findings suggest an inherited susceptibility to develop metastatic breast cancer may affect both the cancer’s aggressiveness and our ability to fight it off. This raises the question of why and how did these inherited differences occur. The current theory appears to be by “natural selection.” As populations moved north out of Africa into colder climates, their bodies needed to adjust how they make, store, and use energy to survive the winters. Since mitochondria are the primary source for developing our bodies’ energy capabilities, it is likely populations harboring beneficial differences in mtDNA were the ones who survived in colder environments. Technology has since decreased the impact of many environmental pressures on our bodies’ ability to survive. It has also helped increase our lifespans, but unfortunately has also increased our risk of developing age-related diseases, such as cancer and Alzheimer’s disease. This raises the question of whether these differences in mtDNA differentially impact our cells’ ability to respond to disease-promoting factors in our bodies, such as cancer-stimulating signals and inflammation. Our immune system is our body’s primary surveillance system against foreign invaders and abnormal events (e.g., uncontrolled cancer cell growth and spread). Treatments, such as Herceptin, are important scientific advancements that have harnessed and enhanced our immune system’s ability to target these cancers. Recent advances in immunotherapies also hold great promise for improving survival in breast cancer patients. Unfortunately, they have not been as successful yet. Career Goals: This development plan focuses on the overarching challenge of identifying why some breast cancers become metastatic. My ultimate career goal is to eliminate deaths from metastatic breast cancer. I plan on meeting this challenge by defining how the differences in our mitochondria impact our immune system’s ability to target cancer cells and how mtDNA differences lead to variances in patients’ tendency to develop metastatic breast cancer. Through this work, I will receive essential training from one of the leading experts in metastasis research, Dr. Danny Welch, as well as fundamental training in immunology from experts at the University of Kansas Medical Center. This training will help me secure a faculty position at a top research institution, and empower me to become a leader in breast cancer research. Research Impact: This proposal aims to develop biomarkers (a measurable indicator), which identify patients who have breast cancers with an increased susceptibility to metastasize and thus enhancing diagnostic accuracy. This could lead to more precise treatment strategies for patients, reducing the costs for overtreatment and maximizing treatment for those who are at increased risk. By understanding how the differences in our mitochondria impact our immune system’s ability to fight off cancer, we can more e
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810450
Entities
People
- Thomas Beadnell
Organizations
- United States Army
- University of Kansas Medical Center