Epigenetic Characterization of Ovarian Cancer Initiating Cells

Ovarian cancer remains one of the most deadly cancers in women. The etiology is unknown, and the poor outcome has been staggered for decades. Relapse and chemoresistance after initial treatment is common with 5-year survival rate around 20-30%. Thus, it is necessary to develop markers for early detection, patient stratification and novel targeted therapies to counteract such chemo-resistance in this deadly disease. The cancer stem/initiating cell concept may confer the reasons for recurrence and chemoresistance. In our previous CDG grant, we have successfully isolated ovarian cancer initiating cells from human cancer tissues and cell lines. We further provided the first evidence that a single cell-derived ovarian cancer stem cells (OVCSCs) exhibited translineage-differentiation stem properties and were highly tumorigenic. Epigenetic modifications have been proven to be important in the differentiation of embryonic stem cells. However, the epigenetic modifications of cancer stem cell differentiation have never been investigated. Changes of DNA methylation are becoming potential biomarkers for cancer screening and prognosis prediction. Based on this research track on epigenomics and cancer stem cells, we have identified methylation signatures for prognosis prediction. This success of proof-of-concept experiments encourages us to do a more comprehensive epigenomic analysis. In addition, 5-hydroxymethylcytosine (5hmC) has recently been found in mammalian cells. Our preliminary results also demonstrated this so called” the 6th base” of 5hmC and its regulator Ten-Eleven-translocation (TET) in ovarian cancer, suggesting a never reported oncogenic role in cancer biology. We will expand our epigenetic research of OVCSC to this new frontier. The long-term goal of this project is to identify new diagnostic and therapeutic targets of ovarian cancer through cancer stem/initiating cells research. We will focus more on epigenetic/epigenomic approaches. Aim 1: Biomarker and drug target discovery through integrated profiling of ovarian cancer stem cells (OVCSCs) Aim 1.1: To establish an OVCSC differentiation model Aim 1.2: Methylomic and gene expression profiling of OVCSC differentiation Aim 1.3: To identify targets through biological network analysis using bioinformatics Aim 1.4: To verify and validate potential DNA methylation biomarkers Aim 1.5: To characterize biological functions of potential therapeutic targets Aim2: To investigate the role of TET1 in ovarian cancer (stem) cells. Aim 2-1: To test the clinical association of TETs in ovarian cancer. Aim 2-2: To assess effect of TET1 on malignant phenotypes in ovarian (stem) cancer cells. Aim 2-3: To investigate whether TET1 facilitate the acquisition of stemness properties through hydroxylase-dependent manner in ovarian cancer cells. Aim 3: To identify potential therapeutic targets through TET1-mediated network in ovarian cancer. Aim3-1: To profile the methylome, hydroxylmethylome as well as transcriptome in ovarian cancer cell lines with or without TET1. Aim3-2: To analysis TET1-mediated regulation network for candidate genes selection. Aim3-3: To validate candidate genes in clinical ovarian cancer tissues. Aim3-4: To test the therapeutic potential of targeting TET1-related molecules in ovarian cancer cells. Understanding these epigenetic characteristics through OVCSC research will have an excellent chance to discover new biomarkers and novel therapeutics, which may fill the unsolved gap and provide the unmatched need of ovarian cancer patients.