Cytotoxic capacity of a novel glycosylated antitumor ether lipid in chemotherapy-resistant high grade serous ovarian cancer in vitro and 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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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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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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EP822 Simvastatin enhances the anti-tumoral effect of metronomic cyclophosphamide against cancer-initiating cells (CICs) by reducing ALDH1A1 expression both in vitro and in vivo: an effective combination to overcome resistance and limit the spread of the recurrent disease in high-grade serous ovarian cancer (HGSOC)

10.1136/ijgc-2019-esgo.872 ◽

2019 ◽

Author(s):

MA Cuello ◽

MF Liberona ◽

S Kato ◽

J Cerda-Infante ◽

C Ibañez ◽

...

Keyword(s):

Ovarian Cancer ◽

Recurrent Disease ◽

High Grade ◽

Serous Ovarian Cancer ◽

Effective Combination ◽

Metronomic Cyclophosphamide

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ZIP4 Is a Novel Cancer Stem Cell Marker in High-Grade Serous Ovarian Cancer

Cancers ◽

10.3390/cancers12123692 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3692

Author(s):

Qipeng Fan ◽

Wen Zhang ◽

Robert E. Emerson ◽

Yan Xu

Keyword(s):

Ovarian Cancer ◽

Stem Cell ◽

Cancer Stem Cell ◽

Stem Cell Marker ◽

High Grade ◽

Serous Ovarian Cancer ◽

Upstream Regulator ◽

Genetic Compensation

High-grade serous ovarian cancer (HGSOC) is one of the most deadly and heterogenic cancers. We have recently shown that ZIP4 (gene name SLC39A4), a zinc transporter, is functionally involved in cancer stem cell (CSC)-related cellular activities in HGSOC. Here, we identified ZIP4 as a novel CSC marker in HGSOC. Fluorescence-activated cell sorter (FACS)-sorted ZIP4+, but not ZIP4− cells, formed spheroids and displayed self-renewing and differentiation abilities. Over-expression of ZIP4 conferred drug resistance properties in vitro. ZIP4+, but not ZIP4− cells, formed tumors/ascites in vivo. We conducted limiting dilution experiments and showed that 100–200 ZIP4+ cells from both PE04 and PEA2 cells formed larger tumors than those from 100–200 ALDH+ cells in mice. Mechanistically, we found that ZIP4 was an upstream regulator of another CSC-marker, NOTCH3, in HGSOC cells. NOTCH3 was functionally involved in spheroid formation in vitro and tumorigenesis in vivo in HGSOC. Genetic compensation studies showed that NOTCH3, but not NOTCH1, was a critical downstream mediator of ZIP4. Furthermore, NOTCH3, but not NOTCH1, physically bound to ZIP4. Collectively, our data suggest that ZIP4 is a novel CSC marker and the new ZIP4-NOTCH3 axis represents important therapeutic targets in HGSOC.

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A Novel ZIP4-HDAC4-VEGFA Axis in High-Grade Serous Ovarian Cancer

Cancers ◽

10.3390/cancers13153821 ◽

2021 ◽

Vol 13 (15) ◽

pp. 3821

Author(s):

Qipeng Fan ◽

Lihong Li ◽

Tian-Li Wang ◽

Robert E. Emerson ◽

Yan Xu

Keyword(s):

Ovarian Cancer ◽

Histone Deacetylase Inhibitors ◽

Hypoxia Inducible Factor ◽

High Grade ◽

Serous Ovarian Cancer ◽

Highly Effective ◽

Endothelial Growth Factor ◽

Targeting Strategy

We have recently identified ZIP4 as a novel cancer stem cell (CSC) marker in high-grade serous ovarian cancer (HGSOC). While it converts drug-resistance to cisplatin (CDDP), we unexpectedly found that ZIP4 induced sensitization of HGSOC cells to histone deacetylase inhibitors (HDACis). Mechanistically, ZIP4 selectively upregulated HDAC IIa HDACs, with little or no effect on HDACs in other classes. HDAC4 knockdown (KD) and LMK-235 inhibited spheroid formation in vitro and tumorigenesis in vivo, with hypoxia inducible factor-1 alpha (HIF1α) and endothelial growth factor A (VEGFA) as functional downstream mediators of HDAC4. Moreover, we found that ZIP4, HDAC4, and HIF1α were involved in regulating secreted VEGFA in HGSOC cells. Furthermore, we tested our hypothesis that co-targeting CSC via the ZIP4-HDAC4 axis and non-CSC using CDDP is necessary and highly effective by comparing the effects of ZIP4-knockout/KD, HDAC4-KD, and HDACis, in the presence or absence of CDDP on tumorigenesis in mouse models. Our results showed that the co-targeting strategy was highly effective. Finally, data from human HGSOC tissues showed that ZIP4 and HDAC4 were upregulated in a subset of recurrent tumors, justifying the clinical relevance of the study. In summary, our study provides a new mechanistic-based targeting strategy for HGSOC.

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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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Credentialing and Pharmacologically Targeting PTP4A3 Phosphatase as a Molecular Target for Ovarian Cancer

Biomolecules ◽

10.3390/biom11070969 ◽

2021 ◽

Vol 11 (7) ◽

pp. 969

Author(s):

John S. Lazo ◽

Elizabeth R. Sharlow ◽

Robert Cornelison ◽

Duncan J. Hart ◽

Danielle C. Llaneza ◽

...

Keyword(s):

Ovarian Cancer ◽

Cell Migration ◽

Tyrosine Phosphatase ◽

In Vitro Cytotoxicity ◽

Mrna Levels ◽

High Grade ◽

Drug Resistant ◽

Ovca Cell

High grade serous ovarian cancer (OvCa) frequently becomes drug resistant and often recurs. Consequently, new drug targets and therapies are needed. Bioinformatics-based studies uncovered a relationship between high Protein Tyrosine Phosphatase of Regenerating Liver-3 (PRL3 also known as PTP4A3) expression and poor patient survival in both early and late stage OvCa. PTP4A3 mRNA levels were 5–20 fold higher in drug resistant or high grade serous OvCa cell lines compared to nonmalignant cells. JMS-053 is a potent allosteric small molecule PTP4A3 inhibitor and to explore further the role of PTP4A3 in OvCa, we synthesized and interrogated a series of JMS-053-based analogs in OvCa cell line-based phenotypic assays. While the JMS-053 analogs inhibit in vitro PTP4A3 enzyme activity, none were superior to JMS-053 in reducing high grade serous OvCa cell survival. Because PTP4A3 controls cell migration, we interrogated the effect of JMS-053 on this cancer-relevant process. Both JMS-053 and CRISPR/Cas9 PTP4A3 depletion blocked cell migration. The inhibition caused by JMS-053 required the presence of PTP4A3. JMS-053 caused additive or synergistic in vitro cytotoxicity when combined with paclitaxel and reduced in vivo OvCa dissemination. These results indicate the importance of PTP4A3 in OvCa and support further investigations of the lead inhibitor, JMS-053.

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