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| Open AccessPlatelets reduce anoikis and promote metastasis by activating YAP1 signaling
Platelets have been associated with increased tumor growth and metastasis but the mechanistic details of this interaction are still unclear. Here the authors show that platelets improve anoikis resistance of cancer cells and increase metastasis by activating Yap through a RhoA/MYPT-PP1 pathway.
- Monika Haemmerle
- , Morgan L. Taylor
- & Anil K. Sood
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| Open AccessMICU1 drives glycolysis and chemoresistance in ovarian cancer
The mitochondrial uniporter MICU1 regulates mitochondrial Ca2+ uptake. Here, the authors show that MICU1 is upregulated in ovarian cancer and confers resistance to cisplatin-induced apoptosis through a Ca2+-mediated regulation of pyruvate dehydrogenase activity that results in increased glycolysis.
- Prabir K. Chakraborty
- , Soumyajit Banerjee Mustafi
- & Priyabrata Mukherjee
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| Open AccessMalignant extracellular vesicles carrying MMP1 mRNA facilitate peritoneal dissemination in ovarian cancer
Ovarian cancer is particularly deadly because it is difficult to detect at the pre-metastatic stage; extracellular vesicles (EVs) on the other hand are involved in the pre-metastatic niche preparation. Here the authors show that EVs mediate ovarian cancer metastasis in the peritoneal area by targeting the mesothelium.
- Akira Yokoi
- , Yusuke Yoshioka
- & Takahiro Ochiya
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| Open AccessAmplification of USP13 drives ovarian cancer metabolism
Cancer cells need to reprogramme their metabolism to allow rapid cell proliferation. Here, the authors show that USP13is amplified in ovarian cancer and its protein product, a deubiquitinase, drives tumour progression by rewiring the metabolism of cancer cells by stabilising two critical metabolic enzymes.
- Cecil Han
- , Lifeng Yang
- & Xiongbin Lu
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| Open AccessIntegrative proteomic profiling of ovarian cancer cell lines reveals precursor cell associated proteins and functional status
High-grade serous ovarian cancer is the most common and aggressive ovarian cancer, with uncertain cell of origin. Here, the authors undertake a mass spectrometric analysis of 26 cancer cell lines and identify a protein signature that classifies ovarian cancer tissues into epithelial and mesenchymal groups.
- F. Coscia
- , K. M. Watters
- & M. Mann
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| Open AccessEpigenetic reprogramming of fallopian tube fimbriae in BRCA mutation carriers defines early ovarian cancer evolution
Women with germline variants in BRCA genes are predisposed to ovarian cancer. In this study, the authors demonstrate that fimbrial tissue from the ovary, the site of ovarian cancer, in BRCAmutant carriers contains marked DNA methylation changes compared with the proximal region of the ovary.
- Thomas E. Bartlett
- , Kantaraja Chindera
- & Martin Widschwendter
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| Open AccessmiR-424(322) reverses chemoresistance via T-cell immune response activation by blocking the PD-L1 immune checkpoint
Resistance to chemotherapy occurs in many ovarian cancer cases. Here, the authors show that mir-424(322) expression restores the sensitivity of ovarian cancer cells to chemotherapy by blocking the PD-L1 immune checkpoint, and find that combining immunotherapy and chemotherapy has a synergistic effect.
- Shaohua Xu
- , Zhen Tao
- & Ke Chen
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| Open AccessExosomal transfer of stroma-derived miR21 confers paclitaxel resistance in ovarian cancer cells through targeting APAF1
The tumor microenviroment can influence cancer progression and response to therapy. In this study, the authors show that miR21 is transferred through exosomes from cancer-associated fibroblasts and adipocytes to ovarian cancer cells where it modulates drug resistance by its direct target APAF1.
- Chi Lam Au Yeung
- , Ngai-Na Co
- & Samuel C. Mok
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| Open AccessMAP3K8/TPL-2/COT is a potential predictive marker for MEK inhibitor treatment in high-grade serous ovarian carcinomas
The identification of pharmaceutically targetable biomarkers is essential for improving therapeutic options for cancer patients. In this study, the authors identify MAP3K8 as a potential predictive marker for MEK inhibitor treatment in patients with aggressive ovarian cancer.
- Tina Gruosso
- , Camille Garnier
- & Fatima Mechta-Grigoriou
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| Open AccessCis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer
Genome-wide association studies have identified regions which confer risk of high-grade serous epithelial ovarian cancer. Here the authors use expression quantitative train locus analysis to identify candidate genes and functionally characterise them, identifying a role for HOXD9 in ovarian cancer.
- Kate Lawrenson
- , Qiyuan Li
- & Matthew L. Freedman
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| Open AccessRETRACTED ARTICLE: An apoptosis-enhancing drug overcomes platinum resistance in a tumour-initiating subpopulation of ovarian cancer
Despite normalization of the CA125 serum biomarker at the completion of carboplatin therapy the vast majority of patients with high grade serous ovarian cancers relapse. Here, Janzen et al., identify a sub-population of tumor cells that are CA125 negative, cancer initiating and platinum resistant but readily eliminated with the addition of apoptosis enhancing drugs to carboplatin.
- D. M. Janzen
- , E. Tiourin
- & S. Memarzadeh
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Article
| Open AccessPI3K/AKT activation induces PTEN ubiquitination and destabilization accelerating tumourigenesis
Mutations and post-translational modifications of the PI3K/AKT pathway inhibitor PTEN are a feature of many cancers, but these have not been associated with cervical cancer. Here, the authors identify a PI3K/AKT-mediated ubiquitination degradation pathway of PTEN that occurs in patients with cervical cancer.
- Min-Sik Lee
- , Man-Hyung Jeong
- & Jaewhan Song
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| Open AccessCharacterization of twenty-five ovarian tumour cell lines that phenocopy primary tumours
Despite methodological improvements, it remains extremely difficult to routinely establish cell lines from human primary tumours. Here, the authors develop a culture medium that allows efficient cell line establishment and use this to generate 25 ovarian cancer cell lines.
- Tan A. Ince
- , Aurea D. Sousa
- & Gordon B. Mills
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The ZNF304-integrin axis protects against anoikis in cancer
Ovarian cancer is often accompanied by metastases at the time of diagnosis and has a poor survival rate. In this study, Aslan et al.identify a role for ZNF304 in ovarian cancer metastasis and show that the protein transcriptionally regulates β1 integrin, resulting in a reduction in programmed cell death.
- Burcu Aslan
- , Paloma Monroig
- & Gabriel Lopez-Berestein
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| Open AccessSensitive β-galactosidase-targeting fluorescence probe for visualizing small peritoneal metastatic tumours in vivo
Surgical removal of the metastases remains a life-extending approach to ovarian cancer, but the nodules are difficult to detect. Here the authors show that a new cell-permeable probe for β-galactosidase can sensitively and specifically detect peritoneal metastases in mouse models of ovarian cancer.
- Daisuke Asanuma
- , Masayo Sakabe
- & Yasuteru Urano
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Quantitative high throughput screening using a primary human three-dimensional organotypic culture predicts in vivo efficacy
Tumour microenvironment affects the outcome of pharmacological anticancer treatments. Here, Kenny et al. show that organotypic cultures of ovarian cancer cells can recapitulate metastasis. They identify several new compounds that block cancer invasion and metastasis and improve survival in mouse models.
- Hilary A. Kenny
- , Madhu Lal-Nag
- & Ernst Lengyel
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Coexistent ARID1A–PIK3CA mutations promote ovarian clear-cell tumorigenesis through pro-tumorigenic inflammatory cytokine signalling
ARID1A is frequently mutated in ovarian clear-cell carcinoma. Here the authors show that ARID1A loss in mice cooperates with PI3K activation to recapitulate the human disease, and implicate IL-6 signalling as the underlying mechanism.
- Ronald L. Chandler
- , Jeffrey S. Damrauer
- & Terry Magnuson
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| Open AccessGlucocorticoids mediate induction of microRNA-708 to suppress ovarian cancer metastasis through targeting Rap1B
Glucocorticoids show promise for the treatment of ovarian cancer. Here the authors show that glucocorticoids transcriptionally induce the tumour suppressor miR-708, which is downregulated in ovarian cancer, especially in late stages and metastatic tumours.
- Kai-Ti Lin
- , Yu-Ming Yeh
- & Lu-Hai Wang
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| Open AccessNF-κB-induced KIAA1199 promotes survival through EGFR signalling
The cross-talk between constitutively active EGFR- and NF-κB-dependent pathways in cancer is poorly understood. Here, the authors identify KIAA1199 as a BCL3 and NF-κB-regulated protein that is expressed in cervical lesions and promotes tumorigenesis through Plexin A2 binding and regulation of EGFR stability.
- Kateryna Shostak
- , Xin Zhang
- & Alain Chariot
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| Open AccessClearance of persistent HPV infection and cervical lesion by therapeutic DNA vaccine in CIN3 patients
While several human papilloma virus (HPV) vaccines exist, a highly effective vaccine that mediates regression of HPV-induced tumours is lacking. Here the authors show that a therapeutic DNA vaccine-induced HPV-specific polyfunctional CD8 T cell in 7 out of 9 patients who all exhibited complete regression of lesions and viral clearance.
- Tae Jin Kim
- , Hyun-Tak Jin
- & Young Chul Sung
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Calcium-dependent FAK/CREB/TNNC1 signalling mediates the effect of stromal MFAP5 on ovarian cancer metastatic potential
The prognostic significance of stromal cells in ovarian cancer has not been explored. Here the authors show that stromal microfibrillar-associated protein 5 (MFAP5) drives metastasis of ovarian cancer and represents a new a prognostic marker related to decreased survival.
- Cecilia S. Leung
- , Tsz-Lun Yeung
- & Samuel C. Mok
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| Open AccessGenomic analyses of gynaecologic carcinosarcomas reveal frequent mutations in chromatin remodelling genes
Malignant mixed Müllerian tumours are a rare and aggressive gynaecological cancer with poor 5-year survival rates. Here, the authors characterize the mutational landscape of carcinosarcomas and highlight the role of chromatin remodelling dysregulation in carcinosarcoma tumorigenesis.
- Siân Jones
- , Nicolas Stransky
- & Victor E. Velculescu
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Genome-wide association study identifies new susceptibility loci for epithelial ovarian cancer in Han Chinese women
Ovarian cancer is common among women and is the leading cause of death from gynaecological malignancies. Here the authors identify two previously unknown genetic variants that increase the risk of epithelial ovarian cancer in Han Chinese women.
- Kexin Chen
- , Hongxia Ma
- & Qingyi Wei
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2′-OMe-phosphorodithioate-modified siRNAs show increased loading into the RISC complex and enhanced anti-tumour activity
Short interfering siRNAs—siRNAs—have therapeutic potential in the treatment of disease; however, their delivery to target tissues is difficult. Here, Wu et al. chemically modify siRNAs and show that this improves loading into the siRNA silencing machinery and thus efficacy in eliminating cancer cells in mice.
- Sherry Y. Wu
- , Xianbin Yang
- & Anil K. Sood
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Integrated analysis of germline and somatic variants in ovarian cancer
Ovarian cancer is one of the most common cancers in women and has an average 5-year survival of only 43%. Here, Kanchi et al.describe the germline and somatic mutation spectrum in ovarian cancer patients and identify potential risk variants associated with the disease.
- Krishna L. Kanchi
- , Kimberly J. Johnson
- & Li Ding
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| Open AccessmicroRNA-181a has a critical role in ovarian cancer progression through the regulation of the epithelial–mesenchymal transition
Ovarian cancer is often diagnosed at a late stage when metastasis has already occurred. In this study, Parikh et al.show that mir-181a is involved in mediating the epithelial-to-mesenchymal transition in ovarian cancer, leading to activation of the TGF-β signalling pathway and metastasis.
- Aditya Parikh
- , Christine Lee
- & Analisa DiFeo
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FOXL2 posttranslational modifications mediated by GSK3β determine the growth of granulosa cell tumours
The majority of ovarian granulosa tumours harbour the C134W mutation in FOXL2 but the mechanism of tumorigenesis is largely unknown. Here, Kim et al. show that mutant FOXL2 is hyperphosphorylated by GSK3β, which targets the protein for degradation, and find that GSK3β inhibition represses the growth of ovarian granulosa cells.
- Jae-Hong Kim
- , Yong-Hak Kim
- & Jeehyeon Bae
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| Open AccessEvaluating cell lines as tumour models by comparison of genomic profiles
Cell lines are widely used in cancer research to study tumour biology. Here Domcke et al.compare genomic data from ovarian cancer cell lines with those from clinical ovarian tumour samples and identify cell lines that most closely resemble the genomic features of high-grade serous ovarian cancer.
- Silvia Domcke
- , Rileen Sinha
- & Nikolaus Schultz
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Gene network reconstruction reveals cell cycle and antiviral genes as major drivers of cervical cancer
As cervical tumours become more invasive, levels of episomal human papillomavirus paradoxically tend to decrease. Here the authors identify a network of antiviral and cell cycle genes that is amplified by chromosomal aberrations and promotes cervical tumour progression.
- Karina L. Mine
- , Natalia Shulzhenko
- & Andrey Morgun
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| Open AccessIdentification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31
Most confirmed susceptibility variants for epithelial ovarian cancer lie in non-protein-coding sequences. Here Permuth-Wey and colleagues investigate variants in 3′ untranslated regions (UTRs) and uncover a new susceptibility locus.
- Jennifer Permuth-Wey
- , Kate Lawrenson
- & Simon A. Gayther
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| Open AccessEpigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer
HNF1B is overexpressed in the clear cell subtype and epigenetically silenced in the serous subtype of ovarian cancer. Pearce and colleagues now show that genetic variants in HNF1B are differentially associated with risks of developing these two cancer subtypes, possibly through an epigenetic mechanism.
- Hui Shen
- , Brooke L. Fridley
- & Celeste Leigh Pearce
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Src activation by β-adrenoreceptors is a key switch for tumour metastasis
The neurotransmitter noradrenaline can regulate cellular processes that contribute to cancer progression, but the underlying mechanisms remain largely unknown. Here the authors identify Src as a key mediator of noradrenaline signalling networks in tumour metastasis.
- Guillermo N. Armaiz-Pena
- , Julie K. Allen
- & Anil K. Sood