CBX2 identified as driver of anoikis escape and dissemination in high grade serous ovarian cancer

Kian Behbakht,Benjamin G Bitler,Monique A Spillman,Lindsay J Wheeler,Zachary L Watson,Miriam D Post,Lubna Qamar,Amber A Berning,Tomomi M Yamamoto

doi:10.1038/s41389-018-0103-1

Abstract

High grade serous ovarian carcinoma (HGSOC) is often diagnosed at an advanced stage. Chromobox 2 (CBX2), a polycomb repressor complex subunit, plays an oncogenic role in other cancers, but little is known about its role in HGSOC. We hypothesize that CBX2 upregulation promotes HGSOC via induction of a stem-like transcriptional profile and inhibition of anoikis. Examination of Gene Expression Omnibus (GEO) datasets and The Cancer Genome Atlas (TCGA) established that increased CBX2 expression conveyed chemoresistance and worse disease-free and overall survival. In primary HGSOC tumors, we observed CBX2 expression was significantly elevated compared to benign counterparts. In HGSOC cell lines, forced suspension promoted CBX2 expression. Subsequently, CBX2 knockdown inhibited anchorage-independent proliferation and potentiated anoikis-dependent apoptosis. Furthermore, CBX2 knockdown re-sensitized cells to platinum-based chemotherapy. Forced suspension promoted increased ALDH activity and ALDH3A1 expression and CBX2 knockdown led to a decrease in both ALDH activity and ALDH3A1 expression. Investigation of CBX2 expression on a HGSOC tissue microarray revealed CBX2 expression was apparent in both primary and metastatic tissues. CBX2 is an important regulator of stem-ness, anoikis escape, HGSOC dissemination, and chemoresistance and potentially serves as a novel therapeutic target.

Highlights

Epithelial ovarian cancer is the deadliest gynecologic malignancy and annually accounts for over 220,000 deaths worldwide[1]
Chromobox 2 (CBX2) is upregulated in high grade serous ovarian cancer and is associated with poor survival We examined CBX2 expression in high-grade serous ovarian carcinoma (HGSOC) in several publicly available datasets (Gene Expression Omnibus; GEO Dataset and The Cancer Genome Atlas; TCGA)
CBX2 is upregulated in HGSOC, high CBX2 expression portends poorer survival, and increased CBX2 expression correlates with platinum resistance

Summary

Introduction

Epithelial ovarian cancer is the deadliest gynecologic malignancy and annually accounts for over 220,000 deaths worldwide[1]. In the US, over 22,000 new cases of ovarian cancer are diagnosed each year and over 14,000 women succumb to the disease[2]. The majority of these cases are classified as high-grade serous ovarian carcinoma (HGSOC). HGSOC tends to be diagnosed at a late stage, when cancer has already spread beyond the pelvis, and Wheeler et al Oncogenesis (2018)7:92 lymphatic or vascular system. As HGSOC cells spread to the abdominal cavity they promote the production of ascites, a collection of intra-peritoneal fluid containing immune cells, tumor cells, and cytokines, along with other cellular and acellular factors[6]. Tumor cells within ascites are hypothesized to be a subpopulation of cells that contribute to disseminated, recurrent, and chemoresistant disease[6]. The genetic drivers of HGSOC dissemination and anchorageindependent survival remain unclear

Methods

Results

Conclusion