Precision radiogenomics: fusion biopsies to target tumour habitats in vivo

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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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

10.1158/1538-7445.am2012-3276 ◽

2012 ◽

Author(s):

Monique Topp ◽

Lynne Hartley ◽

Michele Cook ◽

Dariush Etemadmoghadam ◽

Laura Galleta ◽

...

Keyword(s):

Ovarian Cancer ◽

Mouse Model ◽

Functional Annotation ◽

Clinical Analysis ◽

High Grade ◽

Serous Ovarian Cancer ◽

Xenograft Mouse Model

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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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In vivo synergism between PARP-inhibitor olaparib and HSP90-inhibitor AT13387 in high grade serous ovarian cancer patient derived xenografts.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.15_suppl.e17045 ◽

2016 ◽

Vol 34 (15_suppl) ◽

pp. e17045-e17045 ◽

Cited By ~ 3

Author(s):

Panagiotis Konstantinopoulos ◽

Sangeetha Palakurthi ◽

Qing Zeng ◽

Shan Zhou ◽

Joyce F. Liu ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Patient ◽

Ovarian Cancer Patient ◽

Parp Inhibitor ◽

Hsp90 Inhibitor ◽

High Grade ◽

Serous Ovarian Cancer

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C/EBPβ promotes poly(ADP-ribose) polymerase inhibitor resistance by enhancing homologous recombination repair in high-grade serous ovarian cancer

Oncogene ◽

10.1038/s41388-021-01788-4 ◽

2021 ◽

Author(s):

Jiahong Tan ◽

Xu Zheng ◽

Mengchen Li ◽

Fei Ye ◽

Chunyan Song ◽

...

Keyword(s):

Ovarian Cancer ◽

Homologous Recombination ◽

Parp Inhibitors ◽

High Grade ◽

Serous Ovarian Cancer ◽

Enhancer Binding Protein ◽

Recombination Repair ◽

Inhibitor Resistance

AbstractPARP inhibitors (PARPi) are efficacious in treating high-grade serous ovarian cancer (HG-SOC) with homologous recombination (HR) deficiency. However, they exhibit suboptimal efficiency in HR-proficient cancers. Here, we found that the expression of CCAAT/enhancer-binding protein β (C/EBPβ), a transcription factor, was inversely correlated with PARPi sensitivity in vitro and in vivo, both in HR-proficient condition. High C/EBPβ expression enhanced PARPi tolerance; PARPi treatment in turn induced C/EBPβ expression. C/EBPβ directly targeted and upregulated multiple HR genes (BRCA1, BRIP1, BRIT1, and RAD51), thereby inducing restoration of HR capacity and mediating acquired PARPi resistance. C/EBPβ is a key regulator of the HR pathway and an indicator of PARPi responsiveness. Targeting C/EBPβ could induce HR deficiency and rescue PARPi sensitivity accordingly. Our findings indicate that HR-proficient patients may benefit from PARPi via targeting C/EBPβ, and C/EBPβ expression levels enable predicting and tracking PARPi responsiveness during treatment.

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