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| Open AccessMolecular stratification of endometrioid ovarian carcinoma predicts clinical outcome
The molecular classification of endometroid ovarian carcinomas (EnOC) has not been established, preventing the development of stratified therapeutic approaches. Here the authors characterise the molecular landscape of EnOC by whole exome sequencing, identifying clinically distinct disease subtypes.
- Robert L. Hollis
- , John P. Thomson
- & C. Simon Herrington
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Article
| Open AccessCombining PARP with ATR inhibition overcomes PARP inhibitor and platinum resistance in ovarian cancer models
Patients with ovarium cancer frequently develop resistance to platinum chemotherapy and PARP inhibitors (PARPi). Here, the authors show that the combination of PARP and ATR inhibitors increases the therapeutic response in PARPi and platinum resistant ovarium cancer PDX models.
- Hyoung Kim
- , Haineng Xu
- & Fiona Simpkins
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Article
| Open AccessITLN1 modulates invasive potential and metabolic reprogramming of ovarian cancer cells in omental microenvironment
Advanced ovarian cancer usually spreads to the omentum. Here, the authors show that circulating intelectin-1 (ITLN1) has prognostic significance in patients with advanced ovarian cancer, and that mesothelial cell-derived ITLN1 in the omental tumor microenvironment suppresses ovarian cancer progression.
- Chi-Lam Au-Yeung
- , Tsz-Lun Yeung
- & Samuel C. Mok
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Article
| Open AccessmiR-181a initiates and perpetuates oncogenic transformation through the regulation of innate immune signaling
The majority of high grade serous ovarian cancers originate from fallopian tube secretory epithelial cells (FTSECs). Here the authors show that miR-181a drives oncogenic transformation in FTSECs through the cooperative inhibition of the tumor suppressor RB1 and of STING, resulting in genomic instability and suppression of intrinsic interferon signaling.
- Matthew Knarr
- , Rita A. Avelar
- & Analisa DiFeo
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Article
| Open AccessAssessing the origin of high-grade serous ovarian cancer using CRISPR-modification of mouse organoids
The relative contribution of fallopian tube (FT) or ovarian surface epithelium (OSE) to high-grade serous ovarian cancer (HG-SOC) development is unclear. Here, the authors establish organoid models from murine oviductal and OSE tissues that allow cancer modeling via CRISPR-Cas9 genome editing, and report a dual origin of murine HG-SOC.
- Kadi Lõhmussaar
- , Oded Kopper
- & Hans Clevers
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Article
| Open AccessHigh-throughput functional evaluation of BRCA2 variants of unknown significance
Many germline variants are found in the BRCA2 gene, some of which pre-dispose women to breast and ovarian cancer. Here, the authors develop a method to determine the functional significance of BRCA2 variants and show that it is comparable to the IARC system of classifying variants.
- Masachika Ikegami
- , Shinji Kohsaka
- & Hiroyuki Mano
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Article
| Open AccessNon-coding somatic mutations converge on the PAX8 pathway in ovarian cancer
The role of non-coding somatic mutations in ovarian cancer is unclear. Here, the authors integrate genomic and epigenomic data from patient samples to show that these mutations frequently converge on the PAX8 transcriptional network.
- Rosario I. Corona
- , Ji-Heui Seo
- & Kate Lawrenson
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Article
| Open AccessThe vaginal microbiota associates with the regression of untreated cervical intraepithelial neoplasia 2 lesions
Persistent infection with human papillomavirus can lead to cervical intraepithelial neoplasia (CIN). Here, the authors profile the vaginal microbiota in a cohort of non-pregnant young women diagnosed with CIN2 and find that absence of Lactobacillusspp. and presence of a diverse population of strict anaerobes associates with a decreased regression of untreated CIN2 lesions.
- Anita Mitra
- , David A. MacIntyre
- & Maria Kyrgiou
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Article
| Open AccessRXRs control serous macrophage neonatal expansion and identity and contribute to ovarian cancer progression
Macrophages can differentiate to perform homeostatic tissue-specific functions. Here the authors show that RXR signalling is critical for large peritoneal macrophage (LPM) expansion during neonatal life and LPM lipid metabolism and survival during adult homeostasis, and that ovarian cancer growth relies on RXR-dependent LPMs.
- María Casanova-Acebes
- , María Piedad Menéndez-Gutiérrez
- & Mercedes Ricote
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Article
| Open AccessExome sequencing of familial high-grade serous ovarian carcinoma reveals heterogeneity for rare candidate susceptibility genes
Around half of the heritability underpinning familial high-grade serous ovarian carcinoma remains unidentified. Here, the authors show that extremely rare protein encoding loss-of-function variants, with a high degree of genetic heterogeneity, may account for some of this missing heritability.
- Deepak N. Subramanian
- , Magnus Zethoven
- & Ian G. Campbell
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Comment
| Open AccessWhy the dual origins of high grade serous ovarian cancer matter
Utilising identical genetic aberrations but targeting different cells, Zhang and colleagues seek to uncover how the cell of origin influences high-grade serous ovarian cancer biology, metastasis and response to treatment.
- Emily K. Colvin
- & Viive M. Howell
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Article
| Open AccessMutations in the HPV16 genome induced by APOBEC3 are associated with viral clearance
The APOBEC mutational signature is prevalent in different tumour types. Here, using HPV16- positive cervical samples, the authors show that the signature is more prevalent in the viral genome of benign or clearing HPV16 infections compared to the viral genomes of the more advanced precancerous lesions or cervical cancer.
- Bin Zhu
- , Yanzi Xiao
- & Lisa Mirabello
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Article
| Open AccessIdentification of recurrent FHL2-GLI2 oncogenic fusion in sclerosing stromal tumors of the ovary
Little is known about the genetics of sclerosing stromal tumor of the ovary, a rare type of sex cord-stromal tumor. Here, the authors use sequencing strategies to show that in a cohort of 26 tumor samples 65% carry a FHL2-GLI2 fusion gene and demonstrate in vitro that the fusion gene has oncogenic properties.
- Sarah H. Kim
- , Arnaud Da Cruz Paula
- & Britta Weigelt
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Article
| Open AccessUterine adenomyosis is an oligoclonal disorder associated with KRAS mutations
Uterine adenomyosis often co-occurs with endometriosis or leiomyoma, but little is known about its molecular underpinnings. Here, the authors show that KRAS mutations are frequent in this disease, which might reduce sensitivity to progestin treatment via epigenetic silencing of the progesterone receptor.
- Satoshi Inoue
- , Yasushi Hirota
- & Hiroyuki Mano
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Article
| Open AccessBRCA1 intronic Alu elements drive gene rearrangements and PARP inhibitor resistance
BRCA1 mutations located within the BRCT domain result in proteasomal degradation and sensitivity to PARP inhibitors (PARPi). Here, the authors report genetic rearrangements in the BRCA1 gene that generate a BRCT-less BRCA1 protein isoform, which avoids degradation and leads to PARPi resistance.
- Yifan Wang
- , Andrea J. Bernhardy
- & Neil Johnson
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Article
| Open AccessClinically relevant molecular subtypes and genomic alteration-independent differentiation in gynecologic carcinosarcoma
Carcinosarcoma of the ovary or uterus comprises both carcinoma and sarcoma elements. Here, the authors perform a multi -omics study of the disease revealing therapeutic possibilities for this rare and aggressive disease.
- Osamu Gotoh
- , Yuko Sugiyama
- & Seiichi Mori
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Article
| Open AccessZC3H18 specifically binds and activates the BRCA1 promoter to facilitate homologous recombination in ovarian cancer
High-grade serous ovarian cancers (HGSOCs) have defects in homologous recombination despite a lack of BRCA1/2 mutations. Here, the authors show that ZC3H18 positively regulates BRCA1 transcription and its loss causes BRCA1 promoter methylation and increased HR deficiency in HGSOCs.
- Arun Kanakkanthara
- , Catherine J. Huntoon
- & Larry M. Karnitz
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Article
| Open AccessMitochondrial supercomplex assembly promotes breast and endometrial tumorigenesis by metabolic alterations and enhanced hypoxia tolerance
Cancer cells rely on mitochondrial respiration to satisfy their metabolic demands. Here the authors show that the mitochondrial supercomplex assembly factor COX7RP is abundantly expressed in breast and endometrial cancer cells and promotes tumor growth and hypoxia tolerance partially by altering levels of the tricarboxylic acid cycle intermediates.
- Kazuhiro Ikeda
- , Kuniko Horie-Inoue
- & Satoshi Inoue
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Article
| Open AccessARID1A promotes genomic stability through protecting telomere cohesion
Cells with ARID1A mutations exhibit mitotic defects, yet show surprisingly low levels of copy number defects. Here, Zhao et al. resolve this issue by showing that ARID1A loss causes defects in telomere cohesion, which selects against gross alterations in copy number.
- Bo Zhao
- , Jianhuang Lin
- & Rugang Zhang
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Article
| Open AccessThe molecular origin and taxonomy of mucinous ovarian carcinoma
Whether mucinous ovarian carcinoma (MOC) arises from cells at the ovary or from metastases from other primary sites is an unanswered question. Here, Cheasley et al perform a genetic analysis of the disease, showing that MOC arises at the ovary.
- Dane Cheasley
- , Matthew J. Wakefield
- & Kylie L. Gorringe
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Article
| Open AccessARID1A and PI3-kinase pathway mutations in the endometrium drive epithelial transdifferentiation and collective invasion
PIK3CA mutations and ARID1A loss co-exist in endometrial neoplasms. Here, the authors show that these co-mutations drive gene expression profiles correlated with differential chromatin accessibility and ARID1A binding in the endometrial epithelium, resulting in partial EMT and myometrial invasion.
- Mike R. Wilson
- , Jake J. Reske
- & Ronald L. Chandler
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Article
| Open Accessβ-arrestin1/YAP/mutant p53 complexes orchestrate the endothelin A receptor signaling in high-grade serous ovarian cancer
YAP and mutant p53 crosstalk to regulate transcriptional processes in cancers. Here, the authors show that endothelin-1 mediated activation of β-arrestin interacts with YAP to recruit mutant p53 to the TEAD/YAP complex to promote metastasis and chemoresistance in ovarian cancer.
- Piera Tocci
- , Roberta Cianfrocca
- & Anna Bagnato
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Article
| Open AccessInactivating mutations and X-ray crystal structure of the tumor suppressor OPCML reveal cancer-associated functions
OPCML is a tumour suppressor gene that is epigenetically silenced in ovarian cancer and is somatically mutated in various cancers. Here, the authors solve the X-ray crystal structure of OPCML and model clinically relevant mutations that could contribute to tumorigenesis.
- James R. Birtley
- , Mohammad Alomary
- & Hani Gabra
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Article
| Open AccessSmall extracellular vesicles containing arginase-1 suppress T-cell responses and promote tumor growth in ovarian carcinoma
Cancer cells employ a variety of ways to escape the immune system. Here, the authors show that ovarian cancer cells produce small extracellular vescicles containing arginase 1 that are taken up by dendritic cells in the draining lymph nodes, resulting in inhibition of antigen-specific T-cell proliferation.
- Malgorzata Czystowska-Kuzmicz
- , Anna Sosnowska
- & Jakub Golab
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Article
| Open AccessRan promotes membrane targeting and stabilization of RhoA to orchestrate ovarian cancer cell invasion
Ran, a nucleus-cytoplasm shuttle protein, is implicated in cancer development and survival. Here, the authors show that Ran binds RhoA to impair its degradation and allow its localisation to the plasma membrane of ovarian cancer cells for tumour invasion.
- Kossay Zaoui
- , Zied Boudhraa
- & Anne-Marie Mes-Masson
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Article
| Open AccessA GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis
Clear-cell carcinomas are aggressive tumours characterised by high accumulation of lipids and glycogen. Here, the authors report that these cancers have a common vulnerability to GPX4 inhibition-induced ferroptosis and using CRISPR screen and lipodomic profiling, they identify HIF-2α- HILPDA axis promotes ferroptosis via enrichment of PUFA lipids.
- Yilong Zou
- , Michael J. Palte
- & Stuart L. Schreiber
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Article
| Open AccessMultiple ABCB1 transcriptional fusions in drug resistant high-grade serous ovarian and breast cancer
ABCB1 encodes Multidrug Resistance Protein which promotes efflux of chemotherapeutic and targeted agents. Here, in breast and ovarian cancer the authors identify multiple transcriptional fusion partners involving ABCB1 that are associated with treatment failure and previous treatment regimens.
- Elizabeth L. Christie
- , Swetansu Pattnaik
- & David D. L. Bowtell
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Article
| Open AccessA mathematical-descriptor of tumor-mesoscopic-structure from computed-tomography images annotates prognostic- and molecular-phenotypes of epithelial ovarian cancer
Radiomics—the quantification of features within tumor images—has shown prognostic potential in cancer. Here, the authors use a machine learning approach to develop a radiomic-based small set of descriptors to predict ovarian cancer patient survival based on CT scans acquired pre-operatively in 364 patients.
- Haonan Lu
- , Mubarik Arshad
- & Eric O. Aboagye
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Article
| Open AccessCDK4/6 inhibitors target SMARCA4-determined cyclin D1 deficiency in hypercalcemic small cell carcinoma of the ovary
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is driven by SMARCA4 loss. Here the authors demonstrate that SCCOHT cells are highly sensitive to CDK4/6 inhibition and provide mechanistic insights, whereby this druggable vulnerability is driven by cyclin D1 deficiency induced by SMARCA4 loss.
- Yibo Xue
- , Brian Meehan
- & Sidong Huang
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Article
| Open AccessA recurrent cancer-associated substitution in DNA polymerase ε produces a hyperactive enzyme
Somatic alterations in the exonuclease domain of DNA polymerase ɛ have been linked to the development of highly mutated cancers. Here, the authors report that a major consequence of the most common cancer-associated Polɛ variant is a dramatically increased DNA polymerase activity.
- Xuanxuan Xing
- , Daniel P. Kane
- & Polina V. Shcherbakova
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Article
| Open AccessNuclear lactate dehydrogenase A senses ROS to produce α-hydroxybutyrate for HPV-induced cervical tumor growth
High-risk human papilloma virus (HR-HPV) infection is strongly associated with cervical cancer and current evidences link E7 to HPV-associated carcinogenesis. Here the authors propose a model in which the infection of epithelial cells with high risk HPV results in a burst of reactive oxygen species, translocation of LDHA to the nucleus and activation of a gene profile that supports the growth of cervical cancer.
- Yuan Liu
- , Ji-Zheng Guo
- & Qun-Ying Lei
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Article
| Open AccessIntegrated extracellular microRNA profiling for ovarian cancer screening
Screening methods for early detection of ovarian cancer is technically difficult. Here, the authors investigated circulating microRNA in human blood serum and developed a model using 10 microRNAs to discern between ovarian cancer and being ovarian tumors, solid tumors, and non-cancer patients.
- Akira Yokoi
- , Juntaro Matsuzaki
- & Takahiro Ochiya
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Article
| Open AccessSWI/SNF catalytic subunits’ switch drives resistance to EZH2 inhibitors in ARID1A-mutated cells
The mechanism of resistance to EZH2 inhibitors in cancers with inactivating SWI/SNF mutations is unknown. Here, the authors demonstrate that the switch of the SWI/SNF catalytic subunits from SMARCA4 to SMARCA2 drives resistance to EZH2 inhibitors in ARID1A-mutated ovarian cancer cells.
- Shuai Wu
- , Nail Fatkhutdinov
- & Rugang Zhang
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Article
| Open AccessMethylation of all BRCA1 copies predicts response to the PARP inhibitor rucaparib in ovarian carcinoma
Around 10% of high-grade serous ovarian carcinomas (HGSOC) harbor BRCA1 promoter methylation, but it is uncertain how it predicts response to PARP inhibition. Here, the authors show that homozygous BRCA1 methylation predicts response to rucaparib while heterozygous methylation of BRCA1 predicts resistance in HGSOC.
- Olga Kondrashova
- , Monique Topp
- & Clare L. Scott
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Article
| Open AccessMicroenvironmental niche divergence shapes BRCA1-dysregulated ovarian cancer morphological plasticity
Cancer cells can actively engage in overcoming microenvironmental constraints such as tissue stiffness through adapting their shapes; however it is unclear how microenvironmental cells shape cancer nuclear morphology in human tumors in situ. Here the authors merge machine learning, digital pathology and spatial statistics to study this issue; furthermore the authors identify decreased immune infiltration in the surrounding of diversified cancer cells in a subset of ovarian tumors.
- Andreas Heindl
- , Adnan Mujahid Khan
- & Yinyin Yuan
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Article
| Open AccessIdentification of nine new susceptibility loci for endometrial cancer
Endometrial cancer is the most common invasive gynaecological cancer in developed countries. Here a meta-analysis identifies an additional nine novel endometrial cancer risk loci and eQTL analysis reveals risk variants associate with reduced expression of negative regulators of oncogenic signal transduction proteins.
- Tracy A. O’Mara
- , Dylan M. Glubb
- & Deborah J. Thompson
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Article
| Open AccessFABP4 as a key determinant of metastatic potential of ovarian cancer
In ovarian cancer, metastatic phenotype may impact surgical outcomes. Here, the authors show miR-409-3p regulates FABP4 which can increase metastatic potential of ovarian cancer, and treatment with DOPC nanoliposomes containing either miR-409--3p mimic or FABP4 siRNA inhibits tumor progression in mice.
- Kshipra M. Gharpure
- , Sunila Pradeep
- & Anil K. Sood
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Article
| Open AccessKMT2D/MLL2 inactivation is associated with recurrence in adult-type granulosa cell tumors of the ovary
Adult-type granulosa cell tumors of the ovary (aGCTs) are rare and recurrence is difficult to treat. Here, the authors observe in aGCT a novel recurrent somatic truncating mutation of KMT2D, more frequent in recurrent aGCT, and also non-genetic loss of KMT2D expression.
- R. Tyler Hillman
- , Joseph Celestino
- & P. Andrew Futreal
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Article
| Open AccessC/EBPβ enhances platinum resistance of ovarian cancer cells by reprogramming H3K79 methylation
In ovarian cancer, the mechanism of chemoresistance is a key question. Here, the authors demonstrate that C/EBPβ and DOT1L together increase methylation of H3K79, which upregulates expression of oncogenic genes and drives poor platinum response and poor survival in ovarian cancer.
- Dan Liu
- , Xiao-Xue Zhang
- & Qing-Lei Gao
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Article
| Open AccessSnail promotes ovarian cancer progression by recruiting myeloid-derived suppressor cells via CXCR2 ligand upregulation
Snail is a transcription factor that induces epithelial-mesenchymal transition. Here the authors show that, in the mesenchymal subtype of ovarian cancer, Snail expression promotes tumorigenesis by inducing immune evasion through CXCR2-ligands-mediated recruitment of myeloid-derived suppressor cells.
- Mana Taki
- , Kaoru Abiko
- & Noriomi Matsumura
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Article
| Open AccessUSP15-dependent lysosomal pathway controls p53-R175H turnover in ovarian cancer cells
Gain-of-function mutants of p53 are important for cancer development and strategies to target specifically these isoforms are being investigated. Here the authors report that USP15 is a deubiquitinase specifically regulating p53-R175H levels that can be targeted by a small molecule.
- Achuth Padmanabhan
- , Nicholes Candelaria
- & JoAnne S. Richards
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Article
| Open Accessnc886 is induced by TGF-β and suppresses the microRNA pathway in ovarian cancer
Ovarian cancers often display elevated TGF-β signaling but repressed miRNA expression. Here the authors identify that non-coding RNA nc886 expression is induced by TGF-β, which then binds to DICER and impairs miRNA maturation.
- Ji-Hye Ahn
- , Hyun-Sung Lee
- & Yong Sun Lee
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Article
| Open AccessSensitive and frequent identification of high avidity neo-epitope specific CD8 + T cells in immunotherapy-naive ovarian cancer
Epithelial ovarian cancer (EOC) has low mutational load. Here the authors analyze circulating and tumor-infiltrating lymphocytes (TILs) from 19 EOC patients and report frequent recovery of neo-antigen-reactive T cells from both compartments but with distinct TCR repertoires that have higher affinity in TILs.
- Sara Bobisse
- , Raphael Genolet
- & Alexandre Harari
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Article
| Open AccessmiR200-regulated CXCL12β promotes fibroblast heterogeneity and immunosuppression in ovarian cancers
Cancer-associated fibroblasts (CAFs) are an important part of the tumor microenvironment. Here the authors characterize four subsets of CAFs across human samples of ovarian cancer subtypes and show in the mesenchymal subtype a specific CAF-S1 population that attracts immunosuppressive Tregs via CXCL12β.
- Anne-Marie Givel
- , Yann Kieffer
- & Fatima Mechta-Grigoriou
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Article
| Open AccessCARM1-expressing ovarian cancer depends on the histone methyltransferase EZH2 activity
CARM1 is an arginine methyltransferase often overexpressed in human cancer. Here, the authors show that EZH2 inhibition suppresses growth in CARM1-expressing epithelial ovarian cancer, and examine the mechanism of how CARM1 promotes EZH2-mediated tumor suppressor gene silencing.
- Sergey Karakashev
- , Hengrui Zhu
- & Rugang Zhang
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Article
| Open AccessTuning microtubule dynamics to enhance cancer therapy by modulating FER-mediated CRMP2 phosphorylation
Some anticancer drugs target cell microtubules inhibiting mitosis and cell division. Here, the authors show that CRMP2 induces microtubule bundling and that this activity is regulated by the FER kinase, thus providing a rationale for targeting FER in combination with microtubule-targeting drugs.
- Yiyan Zheng
- , Ritika Sethi
- & Ahmed Ashour Ahmed
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Article
| Open AccessNanoparticle conjugates of a highly potent toxin enhance safety and circumvent platinum resistance in ovarian cancer
Improving the safety and efficacy of chemotherapeutics will help to enhance their effects. Here, the authors show that intraperitoneal delivery of nanoparticle conjugates of a potent toxin prolongs tumor inhibition and survival as compared to cisplatin in advanced-stage and platinum-resistant ovarian cancer mouse models.
- Ruogu Qi
- , Yongheng Wang
- & P. Peter Ghoroghchian
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Article
| Open AccessDecoding critical long non-coding RNA in ovarian cancer epithelial-to-mesenchymal transition
The role of lncRNA is unclear with respect to epithelial-to-mesenchymal transition (EMT), which is linked to ovarian cancer metastasis. Here, the authors show lncRNA DNM3OS expression contributes to ovarian cancer EMT, cell migration/invasion, and correlates with worse overall patient survival.
- Ramkrishna Mitra
- , Xi Chen
- & Christine M. Eischen
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Article
| Open AccessHigh grade serous ovarian carcinomas originate in the fallopian tube
It has previously been proposed that high-grade serous ovarian carcinoma (HGSOC) may originate from the fallopian tube. Here, the authors analyze genetic aberrances in fallopian tube lesions, ovarian cancers, and metastases from HGSOC patients and establish the evolutionary origins of HGSOC in the fallopian tube.
- S. Intidhar Labidi-Galy
- , Eniko Papp
- & Victor E. Velculescu