Novel high-grade serous epithelial ovarian cancer cell lines that reflect the molecular diversity of both the sporadic and hereditary disease

Fleury, Hubert; Communal, Laudine; Carmona, Eurı́dice; Portelance, Lise; Arcand, Suzanna L.; Rahimi, Kurosh; Tonin, Patricia N.; Provencher, Diane; Mes‐Masson, Anne‐Marie

doi:10.18632/genesandcancer.76

Cited by 35 publications

(49 citation statements)

References 80 publications

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“…Intriguingly, HGSOC shares similar genomic features with triple negative breast cancer (TNBC) as per reports from Cancer Genome Atlas (TCGA) Network analysis; in particular, the deregulated pathways characterizing HGSOC are very similar to those in TNBC [ 9 ]. Several independent studies have indicated that HGSOC is associated with very high genomic instability and chromosomal aberrations including intrachromosomal breaks and aneuploidy, which incidentally, also typify and drive intratumoral heterogeneity in TNBC [ 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

A centrosome clustering protein, KIFC1, predicts aggressive disease course in serous ovarian adenocarcinomas

et al. 2016

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BackgroundAmplified centrosomes are widely recognized as a hallmark of cancer. Although supernumerary centrosomes would be expected to compromise cell viability by yielding multipolar spindles that results in death-inducing aneuploidy, cancer cells suppress multipolarity by clustering their extra centrosomes. Thus, cancer cells, with the aid of clustering mechanisms, maintain pseudobipolar spindle phenotypes that are associated with low-grade aneuploidy, an edge to their survival. KIFC1, a nonessential minus end-directed motor of the kinesin-14 family, is a centrosome clustering molecule, essential for viability of extra centrosome-bearing cancer cells. Given that ovarian cancers robustly display amplified centrosomes, we examined the overexpression of KIFC1 in human ovarian tumors.ResultsWe found that in clinical epithelial ovarian cancer (EOC) samples, an expression level of KIFC1 was significantly higher when compared to normal tissues. KIFC1 expression also increased with tumor grade. Our In silico analyses showed that higher KIFC1 expression was associated with poor overall survival (OS) in serous ovarian adenocarcinoma (SOC) patients suggesting that an aggressive disease course in ovarian adenocarcinoma patients can be attributed to high KIFC1 levels. Also, gene expression levels of KIFC1 in high-grade serous ovarian carcinoma (HGSOC) highly correlated with expression of genes driving centrosome amplification (CA), as examined in publically-available databases. The pathway analysis results indicated that the genes overexpressed in KIFC1 high group were associated with processes like regulation of the cell cycle and cell proliferation. In addition, when we performed gene set enrichment analysis (GSEA) for identifying the gene ontologies associated to KIFC1 high group, we found that the first 100 genes enriched in KIFC1 high group were from centrosome components, mitotic cell cycle, and microtubule-based processes. Results from in vitro experiments on well-established in vitro models of HGSOC (OVSAHO, KURAMOCHI), OVCAR3 and SKOV3) revealed that they display robust centrosome amplification and expression levels of KIFC1 was directly associated (inversely correlated) to the status of multipolar mitosis. This association of KIFC1 and centrosome amplification with HGSOC might be able to explain the increased aggressiveness in this disease.ConclusionThese findings compellingly underscore that KIFC1 can be a biomarker that predicts an aggressive disease course in ovarian adenocarcinomas.Electronic supplementary materialThe online version of this article (doi:10.1186/s13048-016-0224-0) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

A centrosome clustering protein, KIFC1, predicts aggressive disease course in serous ovarian adenocarcinomas

et al. 2016

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“…These spontaneously immortalized cell lines have been extensively characterized [22–25]. Among the 18 cell lines, 17 harbor TP53 mutations, which is the most common somatically mutated gene found in HGS EOCs, while the remaining line fails to express TP53 .…”

Section: Resultsmentioning

confidence: 99%

Cumulative defects in DNA repair pathways drive the PARP inhibitor response in high-grade serous epithelial ovarian cancer cell lines

et al. 2016

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PARP inhibitors (PARPi), such as Olaparib, have shown promising results in high-grade serous (HGS) epithelial ovarian cancer (EOC) treatment. PARPi sensitivity has been mainly associated with homologous recombination (HR) deficiency, but clinical trials have shown that predicting actual patient response is complex. Here, we investigated gene expression microarray, HR functionality and Olaparib sensitivity of 18 different HGS EOC cell lines and demonstrate that PARPi sensitivity is not only associated with HR defects. Gene target validation show that down regulation of genes in the nucleotide excision repair (NER) and mismatch repair (MMR) pathways (ERCC8 and MLH1, respectively) increases PARPi response. The highest sensitivity was observed when genes in both the HR and either NER or MMR pathways were concomitantly down regulated. Using clinical samples, patients with these concurrent down regulations could be identified. Based on these results, a novel model to predict PARPi sensitivity is herein proposed. This model implies that the extreme responders identified in clinical trials have deficiencies in HR and either NER or MMR.

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“…The IC 50 's for carboplatin, as determined by clonogenic survival assay, have previously been reported for TOV3041G, TOV112D, and OV866(2) [27,28]. Carboplatin sensitivity for the OV90 cell line was determined in this study using the same clonogenic assay [27]. Briefly, cells were seeded in a 6-well plate at a density of 750 cells/well that allowed the formation of individual colonies.…”

Section: Clonogenic Survival Assaysmentioning

confidence: 86%

“…Three cell lines [TOV112D, OV90, OV866(2)] are classified as resistant to carboplatin therapy in 2D culture as measured by clonogenic assay, and one (TOV3041G) is classified as sensitive ( Table 1). These cell lines were derived in our laboratory from patient tumor (TOV) or ascites (OV) [27,47] samples. All cell lines were authenticated at the beginning of this study using STR profiling by the McGill University Genome Center (Montreal, Canada).…”

Section: Cell Linesmentioning

confidence: 99%

“…There are several methods to prepare 3D spheroids from cell lines (reviewed elsewhere [11,12]) including hanging-droplets [13][14][15][16], rotating wall vessel cultures [14,17], and ultra-low attachment (ULA) 96-well round-bottom plates [11,18,19]. In ovarian cancer, several groups have described the capacity of EOC cell lines to form spheroids by different methodologies [20][21][22][23][24][25][26], including our work using hanging droplets [16,[27][28][29]. These different techniques each have their own challenges.…”

Section: Introductionmentioning

confidence: 99%

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Carboplatin sensitivity in epithelial ovarian cancer cell lines: The impact of model systems

et al. 2020

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Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy in North America, underscoring the need for the development of new therapeutic strategies for the management of this disease. Although many drugs are pre-clinically tested every year, only a few are selected to be evaluated in clinical trials, and only a small number of these are successfully incorporated into standard care. Inaccuracies with the initial in vitro drug testing may be responsible for some of these failures. Drug testing is often performed using 2D monolayer cultures or 3D spheroid models. Here, we investigate the impact that these different in vitro models have on the carboplatin response of four EOC cell lines, and in particular how different 3D models (polydimethylsiloxane-based microfluidic chips and ultra low attachment plates) influence drug sensitivity within the same cell line. Our results show that carboplatin responses were observed in both the 3D spheroid models tested using apoptosis/cell death markers by flow cytometry. Contrary to previously reported observations, these were not associated with a significant decrease in spheroid size. For the majority of the EOC cell lines (3 out of 4) a similar carboplatin response was observed when comparing both spheroid methods. Interestingly, two cell lines classified as resistant to carboplatin in 2D cultures became sensitive in the 3D models, and one sensitive cell line in 2D culture showed resistance in 3D spheroids. Our results highlight the challenges of choosing the appropriate pre-clinical models for drug testing.

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Novel high-grade serous epithelial ovarian cancer cell lines that reflect the molecular diversity of both the sporadic and hereditary disease

Cited by 35 publications

References 80 publications

A centrosome clustering protein, KIFC1, predicts aggressive disease course in serous ovarian adenocarcinomas

A centrosome clustering protein, KIFC1, predicts aggressive disease course in serous ovarian adenocarcinomas

Cumulative defects in DNA repair pathways drive the PARP inhibitor response in high-grade serous epithelial ovarian cancer cell lines

Carboplatin sensitivity in epithelial ovarian cancer cell lines: The impact of model systems

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