A comprehensively characterized cell line panel highly representative of clinical ovarian high-grade serous carcinomas

Abstract

Recent literature suggests that most widely used ovarian cancer (OVCA) cell models do not recapitulate the molecular features of clinical tumors. To address this limitation, we generated 18 cell lines and 3 corresponding patient-derived xenografts predominantly from high-grade serous carcinoma (HGSOC) peritoneal effusions. Comprehensive genomic characterization and comparison of each model to its parental tumor demonstrated a high degree of molecular similarity. Our characterization included whole exome-sequencing and copy number profiling for cell lines, xenografts, and matched non-malignant tissues, and DNA methylation, gene expression, and spectral karyotyping for a subset of specimens. Compared to the Cancer Genome Atlas (TCGA), our models more closely resembled HGSOC than any other tumor type, justifying their validity as OVCA models. Our meticulously characterized models provide a crucial resource for the OVCA research community that will advance translational findings and ultimately lead to clinical applications.

Dysregulation of fibulin-5 and matrix metalloproteases in epithelial ovarian cancer

“…The finding of increased degradation of FBLN5 in EOC tumors led us to consider use of EOC cell lines to investigate regulation of FBLN5. Cytosolic and urea extracts from two commonly used EOC cell lines, HTB77 (SKOV3) and HTB161 (OVCAR3), together with 5 cell lines (Table 1 ) generated at UTSW [ 24 ] were evaluated. FBLN5 was not expressed in any EOC cell line at mRNA or protein level (Figure 2A ).…”

“…Arrows denote migration of endogenous glycosylated FBLN5 (65 kDa) (which is absent in these cells) or purified rFBLN-5 (51 kDa). ( B ) Culture media recovered from EOC cell line 5020 [ 24 ] incubated with vehicle (Ctl) or TGFβ1 (5 μg/ml) for 48 h ± rFBLN5. rFBLN5 was recovered intact with no proteolytic fragments.…”

“…Interestingly, although proMMP-2 was expressed and regulated by TGFβ1, MMP-9 activity was not expressed in SKOV3 or OVCAR3 and was not induced by TGFβ1. In contrast, MMP9 activity was readily detectable in 4 of 5 newly-derived lines (passage 22–25) [ 24 ], and was induced by TGFβ1 (e.g., HCC5020, Figure 4 ).…”

“…Next, we sought to explore the potential function of FBLN5, and more specifically, the physiologic consequence of its degradation in malignant tissues. To answer this question, we turned to cell culture using several ovarian cancer cell lines produced at our institution [ 24 ]. We hypothesized that intact FBLN5 may either inhibit tumor cell-derived MMP-9 or inhibit malignant cell adhesion to native ECM components and thereby protect from local spread of the disease.…”

A living biobank of ovarian cancer ex vivo models reveals profound mitotic heterogeneity

“…Important next steps will be to track genomic and phenotypic evolution during culture establishment and propagation. During the course of this work, additional methodologies were described to establish panels of ovarian cancer models, either as 2D cultures and organoids 35,45,49,50 . Another next step will be to compare genome evolution and CIN in these different culture conditions.…”