Ovarian cancer is the leading cause of death from female reproductive tract cancer. While it is considered as a highly chemo-responsive tumor, the majority of women with high grade serous ovarian cancer experience tumor relapse, associated with chemo-resistance. Ovarian cancer stem cells have been hypothesized to be responsible for poor prognosis, tumor recurrence, and drug resistance of ovarian cancer. Cancer stem cells share some of the normal stem cells’ characteristics, including the ability to self-proliferating, differentiate, and exhibit greatly enhanced tumor initiation capacity. While chemotherapy initially decrease the size of the tumor, residual tumors are enriched in cancer stem cells. To reverse chemo-resistance and prevent tumor relapse, therapies are needed to target rare tumorigenic cancer stem cells. Similar to normal pluripotent cells, in which epigenetic alterations govern gene expression regulating distinct gene expression patterns for specific cell types, we hypothesize that epigenetic rewiring also plays an important role in the maintenance of ovarian cancer stem cells. The goal of this study is to define the epigenetic modification signatures of ovarian cancer stem cells. To achieve my goal, we will use a novel technique label-free, live-cell partial-wave spectroscopic microscopy coupled with a novel sequencing method to reveal the entire physical and molecular regulatory landscape of ovarian cancer stem cells. Our preliminary data support the feasibility of physically detecting epigenetic regulatory landscape of ovarian cancer stem cells sorted from ovarian cancer cells based on their stemness characteristics. We will expand measurements to other representative high-grade serous ovarian cancer cell lines and from primary tumors. To further understand the dynamic changes of the epigenetic regulatory landscape during differentiation, we will perform a time-course assay of ovarian cancer stem cells grown in differentiation medium. In addition, we will also measure the effects of epigenetic modulating agents on the regulatory landscape of ovarian cancer stem cells, to identify the key epigenetic regulators, required for the stemness phenotype. The long-term goal is to characterize the epigenetic regulation of gene signatures in CSCs, allowing the rational design of new treatments to eradicate CSCs.
|Effective start/end date||3/1/18 → 2/28/19|
- Ovarian Cancer Research Fund Alliance (544740)