Abstract 3276: A novel in vivo xenograft mouse model of human high-grade serous ovarian cancer, with clinical, molecular and functional annotation relevant for pre-clinical analysis

Precision radiogenomics: fusion biopsies to target tumour habitats in vivo

British Journal of Cancer ◽

10.1038/s41416-021-01381-2 ◽

2021 ◽

Author(s):

Mireia Crispin-Ortuzar ◽

Evis Sala

Keyword(s):

Ovarian Cancer ◽

Ct Scans ◽

High Grade ◽

Serous Ovarian Cancer ◽

High Degree ◽

Degree Of Heterogeneity

SummaryHigh-grade serous ovarian cancer lesions display a high degree of heterogeneity on CT scans. We have recently shown that regions with distinct imaging profiles can be accurately biopsied in vivo using a technique based on the fusion of CT and ultrasound scans.

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In vivo modeling of metastatic human high-grade serous ovarian cancer in mice

PLoS Genetics ◽

10.1371/journal.pgen.1008808 ◽

2020 ◽

Vol 16 (6) ◽

pp. e1008808 ◽

Cited By ~ 1

Author(s):

Olga Kim ◽

Eun Young Park ◽

David L. Klinkebiel ◽

Svetlana D. Pack ◽

Yong-Hyun Shin ◽

...

Keyword(s):

Ovarian Cancer ◽

High Grade ◽

Serous Ovarian Cancer

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Clinical Value of lncRNA MEG3 in High-Grade Serous Ovarian Cancer

Cancers ◽

10.3390/cancers12040966 ◽

2020 ◽

Vol 12 (4) ◽

pp. 966 ◽

Cited By ~ 2

Author(s):

Marianna Buttarelli ◽

Marta De Donato ◽

Giuseppina Raspaglio ◽

Gabriele Babini ◽

Alessandra Ciucci ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Biology ◽

Tissue Level ◽

High Grade ◽

Serous Ovarian Cancer ◽

Clinical Value ◽

Pre Treatment ◽

Phosphatase And Tensin Homologue

Long non-coding RNAs (lncRNAs) are emerging as regulators in cancer development and progression, and aberrant lncRNA profiles have been reported in several cancers. Here, we evaluated the potential of using the maternally expressed gene 3 (MEG3) tissue level as a prognostic marker in high-grade serous ovarian cancer (HGSOC), the most common and deadliest gynecologic malignancy. To the aim of the study, we measured MEG3 transcript levels in 90 pre-treatment peritoneal biopsies. We also investigated MEG3 function in ovarian cancer biology. We found that high MEG3 expression was independently associated with better progression-free (p = 0.002) and overall survival (p = 0.01). In vitro and in vivo preclinical studies supported a role for MEG3 as a tumor suppressor in HGSOC, possibly through modulation of the phosphatase and tensin homologue (PTEN) network. Overall, results from this study demonstrated that decreased MEG3 is a hallmark for malignancy and tumor progression in HGSOC.

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Development of a Bioluminescent BRCA1-Deficient Xenograft Model of Disseminated, High-Grade Serous Ovarian Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms20102498 ◽

2019 ◽

Vol 20 (10) ◽

pp. 2498

Author(s):

Yen Ting Shen ◽

Lucy Wang ◽

James C. Evans ◽

Christine Allen ◽

Micheline Piquette-Miller

Keyword(s):

Ovarian Cancer ◽

Tumor Growth ◽

Current Model ◽

Intraperitoneal Administration ◽

Xenograft Model ◽

High Grade ◽

Serous Ovarian Cancer ◽

Ovarian Cancer Cell Lines ◽

Resected Tumor

Successful translation of preclinical data relies on valid and comprehensive animal models. While high-grade serous ovarian cancer (HGSOC) is the most prevalent subtype, the most commonly used ovarian cancer cell lines are not representative of HGSOC. In addition, 50% of ovarian cancer patients present with dysfunctional BRCA1/2, however currently there is a shortage of BRCA-deficient models. By utilizing the OVCAR8 cell line, which contains a hypermethylated BRCA1 promoter, the aim of the current study was to establish and characterize an animal model for BRCA-deficient HGSOC. Transfection of the luciferase gene to OVCAR8 cells enabled bioluminescent imaging for real-time, non-invasive monitoring of tumor growth. The resulting model was characterized by peritoneal metastasis and ascites formation at late stages of disease. Immunohistochemical staining revealed high-grade serous histology in all resected tumor nodules. Immunoblotting and qPCR analysis demonstrated BRCA1 deficiency was maintained in vivo. Moderate to strong correlations were observed between bioluminescent signal and tumor weight. Lastly, intraperitoneal administration of carboplatin significantly reduced tumor growth as measured by bioluminescence. The current model demonstrated BRCA1 deficiency and a high resemblance of the clinical features of HGSOC. This model may be well-suited for evaluation of therapeutic efficacy in BRCA-deficient HGSOC.

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A Unique Pattern of Mesothelial-Mesenchymal Transition Induced in the Normal Peritoneal Mesothelium by High-Grade Serous Ovarian Cancer

Cancers ◽

10.3390/cancers11050662 ◽

2019 ◽

Vol 11 (5) ◽

pp. 662 ◽

Cited By ~ 3

Author(s):

Martyna Pakuła ◽

Paweł Uruski ◽

Arkadiusz Niklas ◽

Aldona Woźniak ◽

Dariusz Szpurek ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Specific Pattern ◽

Laboratory Animals ◽

Ovarian Cancer Cells ◽

High Grade ◽

Serous Ovarian Cancer ◽

Mesenchymal Transition

The study was designed to establish whether high aggressiveness of high-grade serous ovarian cancer cells (HGSOCs), which display rapid growth, advanced stage at diagnosis and the highest mortality among all epithelial ovarian cancer histotypes, may be linked with a specific pattern of mesothelial-mesenchymal transition (MMT) elicited by these cells in normal peritoneal mesothelial cells (PMCs). Experiments were performed on primary PMCs, stable and primary ovarian cancer cells, tumors from patients with ovarian cancer, and laboratory animals. Results of in vitro and in vivo tests showed that MMT triggered by HGSOCs (primary cells and OVCAR-3 line) is far more pronounced than the process evoked by cells representing less aggressive ovarian cancer histotypes (A2780, SKOV-3). Mechanistically, HGSOCs induce MMT via Smad 2/3, ILK, TGF-β1, HGF, and IGF-1, whereas A2780 and SKOV-3 cells via exclusively Smad 2/3 and HGF. The conditioned medium from PMCs undergoing MMT promoted the progression of cancer cells and the effects exerted by the cells triggered to undergo MMT by the HGSOCs were significantly stronger than those related to the activity of their less aggressive counterparts. Our findings indicate that MMT in PMCs provoked by HGSOCs is stronger, proceeds via different mechanisms and has more procancerous characteristics than MMT provoked by less aggressive cancer histotypes, which may at least partly explain high aggressiveness of HGSOCs.

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Cytotoxic capacity of a novel glycosylated antitumor ether lipid in chemotherapy-resistant high grade serous ovarian cancer in vitro and in vivo

Translational Oncology ◽

10.1016/j.tranon.2021.101203 ◽

2021 ◽

Vol 14 (11) ◽

pp. 101203

Author(s):

Mark W Nachtigal ◽

Paris Musaphir ◽

Shiv Dhiman ◽

Alon D Altman ◽

Frank Schweizer ◽

...

Keyword(s):

Ovarian Cancer ◽

Ether Lipid ◽

High Grade ◽

Serous Ovarian Cancer

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In vivo tumor growth of high-grade serous ovarian cancer cell lines

Gynecologic Oncology ◽

10.1016/j.ygyno.2015.05.040 ◽

2015 ◽

Vol 138 (2) ◽

pp. 372-377 ◽

Cited By ~ 86

Author(s):

Anirban K. Mitra ◽

David A. Davis ◽

Sunil Tomar ◽

Lynn Roy ◽

Hilal Gurler ◽

...

Keyword(s):

Ovarian Cancer ◽

Tumor Growth ◽

Cell Lines ◽

Cancer Cell ◽

Ovarian Cancer Cell ◽

Cancer Cell Lines ◽

High Grade ◽

Serous Ovarian Cancer ◽

Ovarian Cancer Cell Lines

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Anti-Tumor and Anti-Invasive Effects of ONC201 on Ovarian Cancer Cells and a Transgenic Mouse Model of Serous Ovarian Cancer

10.21203/rs.3.rs-152449/v1 ◽

2021 ◽

Author(s):

Yali Fan ◽

Jiandong Wang ◽

Ziwei Fang ◽

Stuart R Pierce ◽

Lindsay West ◽

...

Keyword(s):

Ovarian Cancer ◽

Mouse Model ◽

Tumor Growth ◽

Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Cellular Stress ◽

Ovarian Cancer Cells ◽

High Grade ◽

Serous Ovarian Cancer ◽

Mesenchymal Transition

Abstract Background: ONC201 is a promising first-in-class small molecule that has been reported to have anti-neoplastic activity in various types of cancer through activation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as well as activation of mitochondrial caseinolytic protease P (ClpP).Methods: Our objective was to evaluate the effect of the ONC201 on (1) proliferation, cellular stress, apoptosis and invasion in human serous ovarian cancer (OC) cell lines, and (2) inhibition of tumor growth in a genetically engineered mouse model of high grade serous OC (K18-gT121+/-;p53fl/fl;Brca1fl/fl; KpB) under obese (high fat diet) and lean (low fat diet) conditions. Results: ONC201 significantly suppressed cell proliferation, induced arrest in G1 phase, and increased cellular stress and apoptosis, accompanied by dual inhibition of the AKT/mTOR/S6 and MAPK pathways in OC cells. ONC201 also resulted in inhibition of adhesion and invasion via epithelial–mesenchymal transition and reduction of VEGF expression. Pre-treatment with the anti-oxidant, N-acetylcysteine (NAC), reversed the ONC201-induced oxidative stress response, and prevented ONC201-reduced VEGF and cell invasion by regulating epithelial–mesenchymal transition protein expression. Knockdown of ClpP in ovarian cancer cells reduced ONC201 mediated the anti-tumor activity and cellular stress. Diet-induced obesity accelerated ovarian tumor growth in the KpB mouse model. ONC201 significantly suppressed tumor growth, and decreased serum VEGF production in obese and lean mice, leading to a decrease in tumoral expression of Ki-67, VEGF and phosphorylation of p42/44 and S6 and an increase in ClpP and DRD5, as assessed by immunohistochemistry. Additionally, ONC201 exhibited greater anti-tumor efficacy in obese (75%) as compared to lean (65%) mice. InterpretationConclusions: These results suggest that ONC206 may be a promising therapeutic agent to be explored in future clinical trials in high grade serous OC.

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