Characterization of Tumor Initiation Using a Novel Mouse Model of High-Grade Serous Ovarian Cancer
Abstract
Early detection remains the most reliable approach for successful treatment of cancer. For ovarian cancer, patients diagnosed with Stage I ovarian cancer experience a 5-year survival of 90%. Unfortunately, the majority (80%) of ovarian cancer patients are diagnosed with advanced-stage high-grade serous ovarian cancer (HGSOC) and have a 5-year survival rate of <30%, due to the limitation of current screening methods. Therefore, the identification of biomarkers for early detection and an understanding of the progressive kinetics of premalignant mutant cells are vitally important to allow physicians to determine precisely when and how to intervene to achieve a more favorable outcome. While information gleaned from research with patient samples and existing mouse models has provided invaluable information about malignant ovarian cancer, including the identification of precursor lesions within the fallopian tube, it remains challenging to visualize, let alone analyze, mutant cells prior to the manifestation of pathological features. Therefore, essentially nothing is known about the molecular events leading from the occurrence of initiating mutations to the development of precursor lesions, the ideal period for developing sensitive and specific biomarkers for early detection. We propose to address this gap in knowledge by developing a novel mouse model for ovarian cancer that can immediately and permanently label mutant cells upon the occurrence of initiating mutations. Using this system, we will first map out the expansion kinetics of tumor-initiating cells in the fallopian tube to gain insights of premalignant tumor progression at an unprecedented temporal and spatial resolution. After we pinpoint the critical time points during early tumor progression, we will purify labeled mutant cells at these time points to identify changes in gene expression in comparison to the normal tissue. Finally, we will validate the most promising biomarkers in a cohort of human precursor lesions and early-stage HGSOC identified by our group. The research team has worked together extensively and includes two basic scientists with expertise in cancer biology and murine genetics, a biomedical engineer who pioneered an approach to evaluate gene expression from limited numbers of cells, a surgical pathologist with ovarian cancer expertise, and a gynecologic oncologist. The successful completion of this application will identify biomarkers prior to the development of pathologically identifiable tumors that can lead to clinical translations for cancer early detection. Ultimately, such information would enable the prevention of ovarian cancer in women, including military personnel and family members.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710174
Entities
People
- Jill Slack-davis
Organizations
- United States Army
- University of Virginia