Characterization of Mutational Status, Spheroid Formation, and Drug Response of a New Genomically-Stable Human Ovarian Clear Cell Carcinoma Cell Line, 105C

Bart Kolendowski,Hal Hirte,Mark Carey,Hiroaki Itamochi,Yudith Ramos Valdes,Wonjae Lee,Trevor G Shepherd,Gabriel E Dimattia

doi:10.3390/cells9112408

Abstract

Ovarian clear cell carcinoma (OCCC) is a rare subtype of gynecological cancer for which well-characterized and authenticated model systems are scarce. We provide an extensive characterization of ‘105C’, a cell line generated from an adenocarcinoma of the clear cell histotype using targeted next-generation sequencing, cytogenetic microarrays, along with analyses of AKT/mTOR signaling. We report that that the 105C cell line is a bona fide OCCC cell line, carrying PIK3CA, PTEN, and ARID1A gene mutations, consistent with OCCC, yet maintain a stable genome as reflected by low copy number variation. Unlike KOC-7c, TOV-21G, and RMG-V OCCC lines also mutated for the above genes, the 105C cells do not carry mutations in mismatch repair genes. Importantly, we show that 105C cells exhibit greater resistance to mTOR inhibition and carboplatin treatment compared to 9 other OCCC cell lines in 3D spheroid cultures. This resistance may be attributed to 105C cells remaining dormant in suspension culture which surprisingly, contrasts with several other OCCC lines which continue to proliferate in long-term suspension culture. 105C cells survive xenotransplantation but do not proliferate and metastasize. Collectively, we show that the 105C OCCC cell line exhibits unique properties useful for the pre-clinical investigation of OCCC pathobiology.

Highlights

Ovarian clear cell cancer (OCCC) is a histotype of epithelial ovarian cancer (EOC) that accounts for 5–10% of all ovarian cancers diagnosed [1,2]
When Ovarian clear cell carcinoma (OCCC) patients present with late stage disease, the outcome is poor because the disease is resistant to conventional epithelial ovarian cancer chemotherapeutics or quickly becomes refractory [10,11,12]
Domcke et al [15] reported a comprehensive molecular analysis of human ovarian cancer cell lines calling into question the origin of some of the most popular human ovarian cancer cell lines cited in the literature

Summary

Introduction

Ovarian clear cell cancer (OCCC) is a histotype of epithelial ovarian cancer (EOC) that accounts for 5–10% of all ovarian cancers diagnosed [1,2]. Elegant studies have shown that endometriotic tissue contiguous with an OCCC lesion contains the same gene mutations characteristic of OCCC. This means that endometriotic tissue is the origin of clear cell cancer of the ovary and is a result of retrograde deposition of this tissue on surfaces within the peritoneal cavity especially the ovary [3,4,5,6]. Anglesio and co-workers [14] have provided a detailed molecular analysis of human ovarian cancer cell lines indicating 7 lines from the CCLE list of 49 human ovarian cancer cell lines as bona fide OCCC lines.

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