Targeting Stromal-to-Tumor Cell Mitochondrial Transfer in Ovarian Cancer Metastasis
Abstract
Lay Abstract: Ovarian cancer is the deadliest gynecologic cancer, killing one U.S. woman every 38 minutes. Early, relentless spread of cancer cells, known as metastasis, is what makes ovarian cancer so deadly. Metastasis is also responsible for the significant symptoms associated with ovarian cancer. Women suffer from nausea, vomiting, malnutrition, pain and bowel obstructions due to cancer cells growing on and within abdominal organs. The ability to stop ovarian cancer metastasis promises to significantly help women with ovarian cancer live better and longer lives. Our overall goal is to understand the steps necessary for metastasis to develop new treatments to stop ovarian cancer spread. New evidence shows that cancer cells do not metastasize by themselves. Cancer cells hijack normal tissue cells to travel with them helping cancer cells grow and spread. This is akin to cancer cell “seeds” acquiring fertile “soil” to successfully grow. This fertile “soil” is generated by a special tissue stem cell called a carcinoma-associated mesenchymal stem cell (CA-MSC). CAMSCs protect cancer cells, supporting their growth and survival through chemotherapy. We discovered that CA-MSCs directly attach to cancer cells and act as a chaperone escorting the cancer cell out of the original cancer site, supporting cancer cell survival during travel, and helping the cancer cell take root in new areas. The ability to help cancer cells spread is dependent on the physical attachment of the CA-MSC to the cancer cell. The CA-MSC attaches to the cancer cell by building a specialized cellular bridge called a tunneling nanotube (TNT). These TNTs are long, thin bridges that connect the two cells even over long distances. These bridges can be open ended, allowing the two cells to share content. Therefore, the formation of these bridges allows for a unique type of cell-to-cell communication. We discovered that CAMSCs use these TNT bridges to donate mitochondria to cancer cells. Mitochondria are the “power houses” of the cell and are necessary to provide the energy cells need to live and grow. CA-MSCs use this TNT connection like a specialized power line to move their own mitochondria to the cancer cell. The specific goal of this project is to understand how CA-MSCs form TNTs with cancer cells to donate mitochondria and to cut these “power lines” to stop cancer spread. We hypothesize that specific proteins on the surface of CA-MSCs and cancer cells form connections necessary for TNT formation and, by disrupting these connections, we will stop TNT formation, mitochondrial transfer, and ultimately ovarian cancer metastasis. To test this hypothesis we propose to: 1. Find which proteins on the CA-MSC and cancer cell surface make up the connections necessary for TNT formation. 2. Determine how CA-MSC to cancer cell mitochondrial donation supports cancer cell spread. 3. Break the TNTs connecting CA-MSCs to cancer cells to stop the spread of ovarian cancer. This pilot proposal will set the stage for future work to develop new treatments for ovarian cancer. Importantly, the process of mitochondrial donation does not appear to be dependent on the genetic background or histologic subtype of ovarian cancer, making therapeutics that target TNT disruption applicable to all women impacted by this deadly disease. By learning how CAMSCs build TNTs to serve as power lines providing cancer cells with mitochondria during the process of metastasis, we can develop new ways to stop ovarian cancer spread and help the over 20,000 U.S. women diagnosed yearly with ovarian cancer live better, longer lives.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110371
Entities
People
- Lan Coffman
Organizations
- United States Army
- University of Pittsburgh