Abstract AS04: Epigenomic characterization of gene regulatory networks in human ovarian cancer stem cells
Authors: Battle Stephanie L. , Larjo Antti , Liao Joling , Lähdesmäki Harri , Lieber Andre , Hawkins R. David 
Published: August 2015

Ovarian cancer is the fifth leading cause of cancer mortality among women in the United States. Despite aggressive surgery and chemotherapy, most patients relapse and develop drug-resistant tumors, leading to the &lt;40% chance of 5 year survival in ovarian cancer patients. Evidence suggests that a small subpopulation of cells in the tumor, ovarian cancer stem cells (OvCSCs), are responsible for tumor relapse and drug resistance. OvCSCs have enhanced tumorigenicity, inherent chemoresistance, and stem-like properties such as the ability to self-renew or divide asymmetrically. These latter characteristics give CSCs an analogous role in tumors that healthy stem cells have in developing organs (adult stem cells) or entire organisms (embryonic stem cells).The goal of this study is to determine how the cancer stem cell state is regulated by annotating the gene regulatory network of OvCSCs. In doing so, we will uncover commonalities that exist between OvCSCs and embryonic or progenitor stem cells.

The epigenome provides the structural framework for cell-type specific gene regulation. Chromatin modifications that uniquely mark gene regulatory elements, like promoters and enhancers, are easily identified throughout the genome using ChIP-seq. ChIP-seq performed in pluripotent stem cells has revealed many epigenetic features that distinguish them from differentiated cells. In an effort to better understand CSC gene regulatory networks, we are generating comprehensive transcriptomic maps and globally identifying enhancers marked by histone 3, lysine 4 monomethylation (via RNAseq and H3K4me1 ChIP-seq respectively) in OvCSCs and their daughter tumor cells. We are also comparing OvCSCs to previously generated data in human embryonic stem cells (hESCs) to identify shared stemness traits. OvCSCs were acquired from patient biopsies and detailed characterization identified a CD133+ CSC population within the tumor. We are using a mouse xenograft model to expand tumors in vivo. Harvested tumors are depleted of blood lineage cells and CD133+ cells (CSCs) are isolated from the remaining cells in the tumor.

Our analysis of RNA-seq and enhancer maps have revealed OvCSC signatures that are absent in tumor cells but present in embryonic stem cells. Many important embryonic stem cell transcription factors are expressed in OvCSCs and have almost identical chromatin enhancer profiles. We identified over 7000 H1 hESC enhancers that have at least 95% overlap with OvCSC enhancers implying a shared regulatory network in these cell types. Motif analysis of nucleosome-free regions within enhancers reveals enrichment for many ESC transcription factors that are also expressed in OvCSCs. Our integrative analysis indicates that OvCSCs share common features of the ESC regulatory network and is beginning to provide novel insight on why CSCs have stem cell properties. We are continuing to build maps for additional histone modifications and genome-wide DNA methylation in OvCSCs to gain a comprehensive view of how the epigenome regulates the cancer stem cell state.

Citation Format: Stephanie L. Battle, Antti Larjo, Joling Liao, Harri Lähdesmäki, Andre Lieber, R. David Hawkins. Epigenomic characterization of gene regulatory networks in human ovarian cancer stem cells [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr AS04.