GATA3 and stemness of high-grade serous ovarian carcinoma: novel hope for the deadliest type of ovarian cancer

Human Cell ◽  
2020 ◽  
Vol 33 (3) ◽  
pp. 904-906 ◽  
Author(s):  
Amr Ahmed El-Arabey ◽  
Mohnad Abdalla ◽  
Adel Rashad Abd-Allah
Keyword(s):  
Ovarian Cancer ◽  
Ovarian Carcinoma ◽  
High Grade ◽  
Serous Ovarian Carcinoma

scholarly journals Mechanisms of Chromosomal Instability in High-grade Serous Ovarian Carcinoma

2019 ◽  
Author(s):  
N. Tamura ◽  
N. Shaikh ◽  
D. Muliaditan ◽  
J. McGuinness ◽  
D. Moralli ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Ovarian Carcinoma ◽  
Single Molecule ◽  
Chromosomal Instability ◽  
Poor Prognosis ◽  
Spindle Assembly Checkpoint ◽  
Western World ◽  
Cancer Type ◽  
High Grade ◽  
Serous Ovarian Carcinoma

AbstractChromosomal instability (CIN), the continual gain and loss of chromosomes or parts of chromosomes, occurs in the majority of cancers and confers poor prognosis. Mechanisms driving CIN remain unknown in most cancer types due to a scarcity of functional studies. High-grade serous ovarian carcinoma (HGSC), the most common subtype of ovarian cancer, is the major cause of death due to gynaecological malignancy in the Western world with chemotherapy resistance developing in almost all patients. HGSC exhibits high rates of chromosome aberrations and knowledge of causative mechanisms is likely to represent an important step towards combating the poor prognosis of this disease. However, very little is known about the nature of chromosomal instability exhibited by this cancer type in particular due to a historical lack of appropriate cell line models. Here we perform the first in-depth functional characterisation of mechanisms driving CIN in HGSC by analysing eight cell lines that accurately recapitulate HGSC genetics as defined by recent studies. We show, using a range of established functional CIN assays combined with live cell imaging and single molecule DNA fibre analysis, that multiple mechanisms co-exist to drive CIN in HGSC. These include supernumerary centrosomes, elevated microtubule dynamics and DNA replication stress. By contrast, the spindle assembly checkpoint was intact. These findings are relevant for developing therapeutic approaches to manipulating CIN in ovarian cancer, and suggests that such approaches may need to be multimodal to combat multiple co-existing CIN drivers.

scholarly journals The metabolic stress-activated checkpoint LKB1-MARK3 axis acts as a tumor suppressor in high-grade serous ovarian carcinoma

2022 ◽  
Vol 5 (1) ◽  
Author(s):  
Hidenori Machino ◽  
Syuzo Kaneko ◽  
Masaaki Komatsu ◽  
Noriko Ikawa ◽  
Ken Asada ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Ovarian Carcinoma ◽  
Cell Cycle Progression ◽  
Target Genes ◽  
Metabolic Stress ◽  
Ovarian Cancer Cells ◽  
Hippo Signaling ◽  
High Grade ◽  
Gynecological Malignancy ◽  
Serous Ovarian Carcinoma

AbstractHigh-grade serous ovarian carcinoma (HGSOC) is the most aggressive gynecological malignancy, resulting in approximately 70% of ovarian cancer deaths. However, it is still unclear how genetic dysregulations and biological processes generate the malignant subtype of HGSOC. Here we show that expression levels of microtubule affinity-regulating kinase 3 (MARK3) are downregulated in HGSOC, and that its downregulation significantly correlates with poor prognosis in HGSOC patients. MARK3 overexpression suppresses cell proliferation and angiogenesis of ovarian cancer cells. The LKB1-MARK3 axis is activated by metabolic stress, which leads to the phosphorylation of CDC25B and CDC25C, followed by induction of G2/M phase arrest. RNA-seq and ATAC-seq analyses indicate that MARK3 attenuates cell cycle progression and angiogenesis partly through downregulation of AP-1 and Hippo signaling target genes. The synthetic lethal therapy using metabolic stress inducers may be a promising therapeutic choice to treat the LKB1-MARK3 axis-dysregulated HGSOCs.

scholarly journals Ovarian Cancer Metastasis to the Larynx: A Case Report and Review of the Literature

2020 ◽  
Vol 2020 ◽  
pp. 1-4
Author(s):  
Chad Purcell ◽  
Ayham Al Afif ◽  
Martin Bullock ◽  
Martin Corsten
Keyword(s):  
Ovarian Cancer ◽  
Ovarian Carcinoma ◽  
World Literature ◽  
Cancer Metastasis ◽  
High Grade ◽  
Review Of The Literature ◽  
Serous Ovarian Carcinoma ◽  
The World ◽  
History Of ◽  
Progressive Dysphagia

Laryngeal secondary malignancies are rare, and most spread locoregionally from hypopharyngeal or thyroid primaries. Metastasis of ovarian carcinoma to the larynx is extremely rare. A 65-year-old woman with a history of high grade serous ovarian carcinoma was undergoing carboplatin chemotherapy for recurrence. She presented with progressive dysphagia and hoarseness; a computer tomography (CT) scan demonstrated bilateral necrotic lymphadenopathy and hypopharyngeal fullness. A hypopharyngeal mass was confirmed on examination, and operative biopsy identified it as high-grade serous ovarian. To our knowledge, this report describes the second immunohistochemically proven metastatic ovarian cancer detected in the larynx in the world literature.

scholarly journals The MEK1/2 Pathway as a Therapeutic Target in High-Grade Serous Ovarian Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1369
Author(s):  
Mikhail S. Chesnokov ◽  
Imran Khan ◽  
Yeonjung Park ◽  
Jessica Ezell ◽  
Geeta Mehta ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Growth ◽  
Ovarian Carcinoma ◽  
Cell Lines ◽  
Tumor Growth Rate ◽  
High Recurrence Rate ◽  
High Grade ◽  
Serous Ovarian Carcinoma

High-grade serous ovarian carcinoma (HGSOC) is the deadliest of gynecological cancers due to its high recurrence rate and acquired chemoresistance. RAS/MEK/ERK pathway activation is linked to cell proliferation and therapeutic resistance, but the role of MEK1/2-ERK1/2 pathway in HGSOC is poorly investigated. We evaluated MEK1/2 pathway activity in clinical HGSOC samples and ovarian cancer cell lines using immunohistochemistry, immunoblotting, and RT-qPCR. HGSOC cell lines were used to assess immediate and lasting effects of MEK1/2 inhibition with trametinib in vitro. Trametinib effect on tumor growth in vivo was investigated using mouse xenografts. MEK1/2 pathway is hyperactivated in HGSOC and is further stimulated by cisplatin treatment. Trametinib treatment causes cell cycle arrest in G1/0-phase and reduces tumor growth rate in vivo but does not induce cell death or reduce fraction of CD133+ stem-like cells, while increasing expression of stemness-associated genes instead. Transient trametinib treatment causes long-term increase in a subpopulation of cells with high aldehyde dehydrogenase (ALDH)1 activity that can survive and grow in non-adherent conditions. We conclude that MEK1/2 inhibition may be a promising approach to suppress ovarian cancer growth as a maintenance therapy. Promotion of stem-like properties upon MEK1/2 inhibition suggests a possible mechanism of resistance, so a combination with CSC-targeting drugs should be considered.

scholarly journals USP19 and RPL23 as Candidate Prognostic Markers for Advanced-Stage High-Grade Serous Ovarian Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 3976
Author(s):  
Haeyoun Kang ◽  
Min Chul Choi ◽  
Sewha Kim ◽  
Ju-Yeon Jeong ◽  
Ah-Young Kwon ◽  
...  
Keyword(s):  
Machine Learning ◽  
Ovarian Cancer ◽  
Ovarian Carcinoma ◽  
Prognostic Markers ◽  
The Cancer Genome Atlas ◽  
Immune Gene ◽  
Mrna Levels ◽  
High Grade ◽  
Advanced Stage ◽  
Serous Ovarian Carcinoma

Ovarian cancer is one of the leading causes of deaths among patients with gynecological malignancies worldwide. In order to identify prognostic markers for ovarian cancer, we performed RNA-sequencing and analyzed the transcriptome data from 51 patients who received conventional therapies for high-grade serous ovarian carcinoma (HGSC). Patients with early-stage (I or II) HGSC exhibited higher immune gene expression than patients with advanced stage (III or IV) HGSC. In order to predict the prognosis of patients with HGSC, we created machine learning-based models and identified USP19 and RPL23 as candidate prognostic markers. Specifically, patients with lower USP19 mRNA levels and those with higher RPL23 mRNA levels had worse prognoses. This model was then used to analyze the data of patients with HGSC hosted on The Cancer Genome Atlas; this analysis validated the prognostic abilities of these two genes with respect to patient survival. Taken together, the transcriptome profiles of USP19 and RPL23 determined using a machine-learning model could serve as prognostic markers for patients with HGSC receiving conventional therapy.

scholarly journals The role of distinct BRD4 isoforms and their contribution to high-grade serous ovarian carcinoma pathogenesis

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Ana Luiza Drumond-Bock ◽  
Magdalena Bieniasz
Keyword(s):  
Ovarian Cancer ◽  
Ovarian Carcinoma ◽  
Transcriptional Control ◽  
Epithelial Mesenchymal Transition ◽  
Genetic Alterations ◽  
High Grade ◽  
Mesenchymal Transition ◽  
Serous Ovarian Carcinoma ◽  
Ovarian Cancer Cell Lines ◽  
Patient Prognosis

AbstractHigh-grade serous ovarian carcinoma (HGSOC) is the most aggressive type of ovarian cancer, often diagnosed at advanced stages. Molecularly, HGSOC shows high degree of genomic instability associated with large number of genetic alterations. BRD4 is the 4th most amplified gene in HGSOC, which correlates with poor patients’ prognosis. BRD4 is constitutively expressed and generates two proteins, BRD4 long (BRD4-L) and BRD4 short (BRD4-S). Both isoforms contain bromodomains that bind to lysine-acetylated histones. Amongst other functions, BRD4 participates in chromatin organization, acetylation of histones, transcriptional control and DNA damage repair. In cancer patients with amplified BRD4, the increased activity of BRD4 is associated with higher expression of oncogenes, such as MYC, NOTCH3 and NRG1. BRD4-driven oncogenes promote increased tumor cells proliferation, genetic instability, epithelial-mesenchymal transition, metastasis and chemoresistance. Ablation of BRD4 activity can be successfully achieved with bromodomain inhibitors (BETi) and degraders, and it has been applied in pre-clinical and clinical settings. Inhibition of BRD4 function has an effective anti-cancer effect, reducing tumor growth whether ablated by single agents or in combination with other drugs. When combined with standard chemotherapy, BETi are capable of sensitizing highly resistant ovarian cancer cell lines to platinum drugs. Despite the evidence that BRD4 amplification in ovarian cancer contributes to poor patient prognosis, little is known about the specific mechanisms by which BRD4 drives tumor progression. In addition, newly emerging data revealed that BRD4 isoforms exhibit contradicting functions in cancer. Therefore, it is paramount to expand studies elucidating distinct roles of BRD4-L and BRD4-S in HGSOC, which has important implications on development of therapeutic approaches targeting BRD4.

scholarly journals Modeling High-grade serous ovarian carcinoma using a combination of in vivo electroporation and CRISPR/Cas9 mediated genome editing

2021 ◽  
Author(s):  
Katie Teng ◽  
Matthew J Ford ◽  
Keerthana Harwalkar ◽  
YuQi Li ◽  
David Farnell ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Ovarian Carcinoma ◽  
Genome Editing ◽  
Mouse Models ◽  
Gynecological Cancer ◽  
Lineage Tracing ◽  
High Grade ◽  
In Vivo Electroporation ◽  
Serous Ovarian Carcinoma

Ovarian cancer remains the most lethal gynecological cancer today. High-grade serous ovarian carcinoma (HGSC) is the most common and lethal type of ovarian cancer and is most frequently diagnosed at advanced stages. Here, we developed a novel strategy to generate somatic ovarian cancer mouse models using a combination of in vivo electroporation and CRISPR/Cas9 mediated genome editing. We mutated tumor suppressor genes associated with HGSC in two different combinations; Brca1, Tp53, Pten with/without Lkb1 and successfully generated HGSC, however, with different latencies and pathophysiology. By utilizing Cre lineage tracing in our system, we visualized peritoneal micrometastases in an immune-competent environment. Because our strategy is flexible in selecting mutation combinations and targeting areas, it would be useful for generating ovarian cancer mouse models.

scholarly journals The MEK1/2 pathway as a therapeutic target in high-grade serous ovarian carcinoma

2019 ◽  
Author(s):  
Mikhail Chesnokov ◽  
Imran Khan ◽  
Yeonjung Park ◽  
Jessica Ezel ◽  
Geeta Mehta ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Growth ◽  
Ovarian Carcinoma ◽  
Cell Lines ◽  
Cancer Cell ◽  
Ovarian Cancer Cell ◽  
High Grade ◽  
Tissue Samples ◽  
Serous Ovarian Carcinoma

AbstractRationaleHigh-grade serous ovarian carcinoma (HGSOC) is the deadliest of gynecological cancers due to high rate of recurrence and acquired chemoresistance. Mutation and activation of the RAS/MAPK pathway has been linked to cancer cell proliferation and therapeutic resistance in numerous cancers. While RAS mutations are not commonly observed in HGSOC, less is known about downstream pathway activation. We therefore sought to investigate the role of MEK1/2 signaling in ovarian cancer.MethodsMEK1/2 pathway activity was evaluated in clinical HGSOC tissue samples and ovarian cancer cell lines by using tissue microarray-based immunohistochemistry, immunoblotting, and RT-qPCR. OVCAR8 and PEO4 HGSOC cell lines were used to assess the effect of MEK1/2 inhibition on cell viability, proliferation rate, and stem-like characteristics. Xenografts were used in mice to investigate the effect of MEK1/2 inhibition on tumor growth in vivo. A drug washout experimental model was used to study the lasting effects of MEK1/2 inhibition therapy.ResultsMEK1/2 signaling is active in a majority of HGSOC tissue samples and cell lines. MEK1/2 is further stimulated by cisplatin treatment, suggesting that MEK1/2 activation may play a role in chemotherapy resistance. The MEK1/2 inhibitor, trametinib, drastically inhibits MEK1/2 downstream signaling activity, causes prominent cell cycle arrest in the G1/0-phase in cell cultures, and reduces the rate of tumor growth in vivo, but does not induce cell death. Cells treated with trametinib display a high CD133+ fraction and increased expression of stemness-associated genes. Transient trametinib treatment causes long-term increases in a high ALDH1 activity subpopulation of cells that possess the capability of surviving and growing in non-adherent conditions.ConclusionsMEK1/2 inhibition in HGSOC cells efficiently inhibits proliferation and tumor growth and therefore may be a promising approach to suppress ovarian cancer cell growth. MEK1/2 inhibition promotes stem-like properties, thus suggesting a possible mechanism of resistance and that a combination with CSC-targeting drugs should be considered.

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