Identifying Targetable Vulnerabilities of Bone Marrow-Derived Adipocytes in the Ovarian Cancer Tumor Microenvironment
Abstract
Older and postmenopausal women are at much higher risk of developing ovarian cancer than younger women, and they often have much more extensive disease and poor treatment outcomes. Ovarian cancer can spread aggressively into adipose (i.e., fat) deposits within the abdomen. It is known that, after menopause, the amount of inner abdominal fat increases. In addition, this fat becomes more inflammatory. It is known that such chronic inflammation can attract cancer cells and increase their growth. It can also reduce the effectiveness of chemotherapy and prevent the body’s own immune system from fighting cancer cells. However, the ultimate source of inflammation within the abdomen in older and postmenopausal women has not been fully described. We believe that some of this inflammation comes from a novel type of fat cells known as bone marrow-derived adipocytes (BMDAs). These cells were discovered in humans by the Co-Investigator of this application. BMDAs differ in several important ways from normal fat cells (which we refer to as CMAs). In mice, BMDAs accumulate in abdominal fat deposits and their production increases with age. Female mice tend to make more BMDAs than male mice. Removal of the ovaries from female mice caused even greater production of BMDAs, showing that loss of ovarian hormones – similar to what happens during menopause – may be a trigger for BMDA production. This has implications for older and postmenopausal women, as they may also have higher BMDA numbers. In further studies, mouse BMDAs were found to release high amounts of inflammatory signals called cytokines. Our data show that human BMDAs also release high amounts of cytokines. These amounts are much higher than those found in CMAs. These cytokines can signal to cancer cells, causing them to migrate and grow or even to become resistant to drugs or to the immune system. We found that ovarian cancer cells grew faster when incubated in secretions from BMDAs. In further experiments in cancer cells, we found increased internal signaling that promotes survival and growth. Together, these data suggest that BMDAs can send chemical signals to ovarian cancer cells and that ovarian cancer cells can respond by increasing their growth rates. Our central idea is that BMDAs promote ovarian cancer, including growth, spread, chemotherapy resistance, and immune evasion. We will perform several experiments to test our hypothesis. First, we will directly compare ovarian cancer growth in normal mice vs. mice that have had all BMDAs removed. These mice still have normal CMAs but lack the highly inflammatory BMDAs. They were developed by a collaborator with extensive experience studying adipocytes, and this experiment will directly show the effect of BMDAs on ovarian cancer growth and spread within a live animal. Second, to show differences in spread and immune response, we will compare migration of ovarian cancer cells and response of human immune cells to secretions from BMDAs and from CMAs. Finally, we will incubate ovarian cancer cells in secretions from BMDAs or CMAs and then compare their sensitivity to a large panel of FDA-approved chemotherapy drugs. We believe that this project is highly innovative, and the expertise of our assembled team is entirely unique. Our results may provide key insights that explain why older and postmenopausal women have worse disease and poor outcomes. BMDAs and their secreted cytokines could be a focus for a new paradigm in therapy development to prevent disease spread, improve chemotherapy responses, as well as help the immune system to kill cancer cells. Our work is strongly aligned with the goals of the OCRP to understand progression of ovarian cancer, improve therapy response, and improve survival and quality of life for Service Members, Veterans, retirees, and all women impacted by ovarian cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210423
Entities
People
- Zachary L Watson
Organizations
- United States Army
- University of Colorado Denver