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| Open AccessAP-1 and TGFß cooperativity drives non-canonical Hedgehog signaling in resistant basal cell carcinoma
Basal cell carcinoma (BCC) cells with increased nuclear myocardin-related transcription factor (nMRTF) levels are resistant to Smoothened inhibitors, however how MRTF activity is regulated is still elusive. Here, the authors identify a LYPD3+/TACSTD2+/LY6D+ BCC subpopulation of resistant BCC cells where AP-1 and TGFß drive nMRTF activation and amplify noncanonical Gli1 activity
- Catherine D. Yao
- , Daniel Haensel
- & Anthony E. Oro
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Article
| Open AccessInterleukin-8 as a candidate for thymoma identification and recurrence surveillance
Imaging methods, such as CT or MRI, cannot provide accurate diagnosis between malignant thymomas and other thymic abnormalities. Here the authors show that the levels of IL-8 in circulating naive T cells are elevated in patients with thymoma compared with other thymic masses, proposing IL-8 as a candidate biomarker for thymoma diagnosis and recurrence surveillance.
- Shilin Gao
- , Jiahao Jiang
- & Jianyong Ding
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Article
| Open AccessTherapeutic paradigm of dual targeting VEGF and PDGF for effectively treating FGF-2 off-target tumors
Anti-VEGF therapy has many limitations that might be resolved by using combination treatment approaches. Here, the authors demonstrate that the dual-targeting of VEGF and PDGF is required for targeting resistant FGF2+ tumors which depend on the recruitment of pericytes on tumor microvessels.
- Kayoko Hosaka
- , Yunlong Yang
- & Yihai Cao
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Article
| Open AccessNon-invasive early detection of cancer four years before conventional diagnosis using a blood test
Patients whose disease is diagnosed in its early stages have better outcomes. In this study, the authors develop a non invasive blood test based on circulating tumor DNA methylation that can potentially detect cancer occurrence even in asymptomatic patients.
- Xingdong Chen
- , Jeffrey Gole
- & Li Jin
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Article
| Open AccessMachine learning of serum metabolic patterns encodes early-stage lung adenocarcinoma
Early diagnosis significantly improves the probability of successful cancer therapy. Here, the authors develop a technique to analyse serum metabolites and define a biomarker panel for early-stage lung adenocarcinoma diagnosis.
- Lin Huang
- , Lin Wang
- & Kun Qian
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Article
| Open AccessSystemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in hosts with cancer
The gut microbiota has been reported to regulate the efficacy of cancer therapy. Here, the authors show that short-chain fatty acids, which are generated through bacterial fermentation, increases immune tolerance leading to resistance to anti-CTLA-4 immunotherapy in mice and patients with metastatic melanoma.
- Clélia Coutzac
- , Jean-Mehdi Jouniaux
- & Nathalie Chaput
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Article
| Open AccessPan-cancer characterization of immune-related lncRNAs identifies potential oncogenic biomarkers
In cancer, long noncoding RNAs (lncRNAs) can regulate immune-related pathways. Here, the authors present ImmLnc, an algorithm that can help prioritise immune-related lncRNAs in cancer immunotherapy research
- Yongsheng Li
- , Tiantongfei Jiang
- & Xia Li
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Article
| Open AccessImmunoproteasome expression is associated with better prognosis and response to checkpoint therapies in melanoma
The response to immunotherapy of melanoma patients is heterogeneous. Here, the authors demonstrate that a high expression of the two major components of the immunoproteasome, PSMB8 and PSMB9, modulates the production of HLA peptides and it is predictive of better survival and improved response to immune-checkpoint inhibitors of melanoma patients.
- Shelly Kalaora
- , Joo Sang Lee
- & Yardena Samuels
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Article
| Open AccessResistance of melanoma to immune checkpoint inhibitors is overcome by targeting the sphingosine kinase-1
There are many patients who do not respond to immune checkpoint inhibitor (ICI) immunotherapy. Here, the authors show a significant negative correlation between sphingosine kinase-1 (SK1) expression and survival for ICI-treated melanoma patients, and further show that targeting SK1 improves response to ICI in mouse cancer models.
- Caroline Imbert
- , Anne Montfort
- & Céline Colacios
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Article
| Open AccessClonal selection confers distinct evolutionary trajectories in BRAF-driven cancers
BRAF mutations are frequent events in many different cancer types. Here, the authors highlight how distinct BRAF mutations affect the clonal dynamics and architecture of emergent tumours, with potential implications for therapeutic intervention.
- Priyanka Gopal
- , Elif Irem Sarihan
- & Mohamed E. Abazeed
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Article
| Open AccessInference of transcription factor binding from cell-free DNA enables tumor subtype prediction and early detection
Deregulation of transcription factors is frequently observed in cancer. Here, the authors develop a blood-based approach to map transcription factor binding, revealing both patient-specific and tumour-specific aberrations
- Peter Ulz
- , Samantha Perakis
- & Michael R. Speicher
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Article
| Open AccessLiquid biopsy tracking during sequential chemo-radiotherapy identifies distinct prognostic phenotypes in nasopharyngeal carcinoma
Liquid biopsies are emerging as a useful method for diagnosis and prognosis in cancer. Here, the authors show the prognostic value of monitoring the level of circulating Epstein-barr virus DNA throughout induction chemotherapy and chemo-radiotherapy and its potential utility for risk-adapted individualised therapy in nasopharyngeal carcinomapatients.
- Jiawei Lv
- , Yupei Chen
- & Ying Sun
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Article
| Open AccessDistinct methylation levels of mature microRNAs in gastrointestinal cancers
In cancer it is assumed that microRNAs recognise and regulate their targets uniformly. Here, the authors show that in gastrointestinal cancers methylation of microRNAs may impact their stability, and that levels of microRNA methylation are distinct in pancreatic cancer patients compared to healthy controls with potential diagnostic implications.
- Masamitsu Konno
- , Jun Koseki
- & Hideshi Ishii
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Article
| Open AccessMethylation analysis of plasma DNA informs etiologies of Epstein-Barr virus-associated diseases
Epstein-Barr virus (EBV) is associated with different malignant diseases and circulating EBV DNA is a biomarker for nasopharyngeal carcinoma (NPC). Here, the authors report that plasma EBV DNA methylation profiles show disease-associated patterns and can help to distinguish NPC and non-NPC subjects.
- W. K. Jacky Lam
- , Peiyong Jiang
- & Y. M. Dennis Lo
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Article
| Open AccessSubtype-specific secretomic characterization of pulmonary neuroendocrine tumor cells
Secreted proteins present a rich resource of potential cancer biomarkers. Here, the authors use mass spectrometry to analyze secretome remodeling in pulmonary neuroendocrine lung cancer cell lines and validate potential biomarkers and therapeutic targets in vitro and in mouse models.
- Xu-Dong Wang
- , Rongkuan Hu
- & Yonghao Yu
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Article
| Open AccessPRKCSH contributes to tumorigenesis by selective boosting of IRE1 signaling pathway
Cancer cells utilise the unfolded protein response (UPR) to adapt to environmental and ER stress. Here, the authors show that the glycosidase II beta subunit, PRKSCH, protects cancer cells from ER stress, by interacting with IRE1α and activating the IRE1α-XBP1 branch of the UPR.
- Gu-Choul Shin
- , Sung Ung Moon
- & Kyun-Hwan Kim
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Article
| Open AccessMultiple myeloma immunoglobulin lambda translocations portend poor prognosis
Multiple myeloma is frequently characterised by translocation of genes next to the immunoglobulin heavy chain locus. In this study, the authors sequence a large cohort of high risk myeloma samples and find translocations of cMyc to the immunoglobulin heavy chain locus and this is associated with poor prognosis.
- Benjamin G. Barwick
- , Paola Neri
- & Lawrence H. Boise
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Article
| Open AccessMolecular subtyping reveals immune alterations associated with progression of bronchial premalignant lesions
Bronchial premalignant lesions can potentially progress to lung squamous cell carcinoma. Here, the authors profile bronchial biopsies from high-risk smokers by RNA sequencing and identify four molecular subtypes of premalignant lesions and an immune molecular signature that associates with lesion progression.
- Jennifer E. Beane
- , Sarah A. Mazzilli
- & Avrum E. Spira
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Article
| Open AccessA serum microRNA classifier for the diagnosis of sarcomas of various histological subtypes
Sarcomas are rare malignant tumours of bone and soft tissue whose diagnosis remain difficult. Here, the authors analyse serum samples from over 1000 patients and using separate discovery, training and validation cohorts, identify and validate a 7-microRNA index that distinguishes malignant sarcomas from benign disease.
- Naofumi Asano
- , Juntaro Matsuzaki
- & Takahiro Ochiya
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Article
| Open AccessABHD5 blunts the sensitivity of colorectal cancer to fluorouracil via promoting autophagic uracil yield
The mechanisms underlying differential chemotherapeutic response to 5-fluorouracil are not fully known. Here, the authors show that ABDH5 regulates sensitivity to 5-fluorouracil in colorectal cancer by regulating lysosome function.
- Juanjuan Ou
- , Yuan Peng
- & Houjie Liang
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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 AccessLocal mutational diversity drives intratumoral immune heterogeneity in non-small cell lung cancer
Intratumoral immunity heterogeneity is poorly characterized. Here the authors apply exome sequencing, transcriptome profiling and T-cell repertoire profiling to multiple loci of non-small-cell lung cancer patients' biopsies and find high spatial immune heterogeneity with local mutational burden correlating with T-cell clonal expansion but not with cytotoxicity.
- Qingzhu Jia
- , Wei Wu
- & Bo Zhu
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Article
| Open AccessSpatially and functionally distinct subclasses of breast cancer-associated fibroblasts revealed by single cell RNA sequencing
Cancer-associated fibroblasts (CAFs) are an important component of the breast tumour microenvironment. Here, single-cell RNA sequencing of CAFs from a mouse model of breast cancer defines three transcriptomically distinct subpopulations with putatively different functions.
- Michael Bartoschek
- , Nikolay Oskolkov
- & Kristian Pietras
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Article
| Open AccessRET rearrangements are actionable alterations in breast cancer
Fusions of the gene RET have been described in thyroid and lung cancers. Here, the AUs identify RET gene alterations, including known fusions, novel fusions, and rearrangements in breast cancer (BC) that are involved in the tumorigenic process and show the benefit of RET therapy in a recurrent BC patient carrying the NCOA4-RET fusion.
- Bhavna S. Paratala
- , Jon H. Chung
- & Kim M. Hirshfield
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Article
| Open AccessColorectal cancer liver metastatic growth depends on PAD4-driven citrullination of the extracellular matrix
Colorectal cancers (CRCs) often develop into untreatable metastatic disease of the liver. Here the authors report the modification of extracellular matrix proteins by citrullination in CRC metastases to the liver and propose that inhibition of citrullination could serve as therapeutic avenue in the treatment.
- A. E. Yuzhalin
- , A. N. Gordon-Weeks
- & R. J. Muschel
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Article
| Open AccessPlasma Tie2 is a tumor vascular response biomarker for VEGF inhibitors in metastatic colorectal cancer
Identification of response biomarkers is a key step towards the development of personalised care. Here, Jayson et al. identify plasma Tie2 as a biomarker for the response of the tumor vasculature to anti-angiogenics in patients with metastatic colorectal cancer, suggesting that monitoring Tie2 levels may help guide therapy in the clinics.
- Gordon C. Jayson
- , Cong Zhou
- & Caroline Dive
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Article
| Open AccessOvercoming EGFRG724S-mediated osimertinib resistance through unique binding characteristics of second-generation EGFR inhibitors
Acquired resistance to targeted drugs remains a major clinical challenge in lung adenocarcinoma patients. Here, the authors show how the acquired EGFRG724S mutation induces resistance to third-generation EGFR inhibitors and why the mutant kinase remains susceptible to second-generation inhibitors.
- Jana Fassunke
- , Fabienne Müller
- & Martin L. Sos
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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 AccessCopy number load predicts outcome of metastatic colorectal cancer patients receiving bevacizumab combination therapy
Increased copy number alterations, indicative of chromosomal instability, is associated with poor cancer outcome. Here, metastatic colorectal cancer patients displaying intermediate-high CIN associate with improved outcome following chemotherapy and bevacizumab treatment, suggesting CIN as a predictive biomarker.
- Dominiek Smeets
- , Ian S. Miller
- & Annette T. Byrne
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Article
| Open AccessCombining discovery and targeted proteomics reveals a prognostic signature in oral cancer
Oral cancer has region-specific histopathological and molecular characteristics, complicating its classification by the standard tumor-node-metastasis system. Here, the authors combine discovery and targeted proteomics with IHC to identify region-specific and saliva biomarkers for oral cancer prognosis.
- Carolina Moretto Carnielli
- , Carolina Carneiro Soares Macedo
- & Adriana Franco Paes Leme
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Article
| Open AccessThe VAR2CSA malaria protein efficiently retrieves circulating tumor cells in an EpCAM-independent manner
Isolation of circulating tumor cells (CTCs) allows for non-invasive disease monitoring and characterization. Here the authors describe an alternative CTC isolation method based on the ability of the malaria rVAR2 protein to specifically bind oncofetal chondroitin sulfate, which is expressed by all cancer cells
- Mette Ø. Agerbæk
- , Sara R. Bang-Christensen
- & Ali Salanti
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Article
| Open AccessCirculating tumor DNA analysis depicts subclonal architecture and genomic evolution of small cell lung cancer
Small cell lung cancer (SCLC) may evolve under treatment. But tumor tissues are often not available to study evolution of SCLC. Here, the authors utilize circulating tumor DNA to investigate the genomic evolution and subclonal architecture of SCLC during therapy.
- Jingying Nong
- , Yuhua Gong
- & Jinghui Wang
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Article
| Open AccessThe genomic landscape of TERT promoter wildtype-IDH wildtype glioblastoma
Glioblastoma can be classified based on IDH and TERT promoter mutations, but ~20% of glioblastoma do not have these mutations (TERTpWT-IDHWT glioblastoma). Here, the authors present a genetic landscape of TERTpWT-IDHWT glioblastoma, identifying a telomerase-positive subgroup driven by TERT-structural rearrangements and an ALT-positive subgroup with mutations in ATRX or SMARCAL1.
- Bill H. Diplas
- , Xujun He
- & Hai Yan
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Article
| Open AccessA serum microRNA signature predicts trastuzumab benefit in HER2-positive metastatic breast cancer patients
Resistance to therapy is a significant issue for patients with metastatic breast cancer (MBC). Here the authors analyze total miRNA from serum samples of 386 MBC patients before treatment with a follow up of 31 months and define a four miRNA signature that predicts the therapeutic benefit of trastuzumab.
- Huiping Li
- , Jiang Liu
- & Erwei Song
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Article
| Open AccessThe LINC01138 drives malignancies via activating arginine methyltransferase 5 in hepatocellular carcinoma
Long intergenic non-coding RNAs have been linked to cancer development. Here the authors, using RNA-seq and genomic amplification data, identify lincRNAs deregulated in hepatocellular carcinoma and propose that Linc01138 is stabilized by IGF2BP1/3 in the cytoplasm, and binds and stabilizes the methyltransferase PRMT5 by preventing the association of PRMT5 to the E3 ubiquitin ligase CHIP.
- Zhe Li
- , Jiwei Zhang
- & Xianghuo He
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Article
| Open AccessMulti-omics analysis reveals neoantigen-independent immune cell infiltration in copy-number driven cancers
Neoantigen load has been associated with tumour immune infiltration. Here, the authors show that while this is true for tumours with recurrent mutations, cancers with recurrent CNAs show neoantigen-independent infiltration driven by cytokine production downstream of the DNA damage sensor ATM.
- Daniel J. McGrail
- , Lorenzo Federico
- & Nidhi Sahni
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Article
| Open AccessEarly circulating tumor DNA dynamics and clonal selection with palbociclib and fulvestrant for breast cancer
Circulating tumor DNA (ctDNA) may provide a prediction of treatment response, but could be impacted by tumor heterogeneity. Here, the authors investigate ctDNA in CDK4/6 inhibitor treatment in advanced breast cancer, finding ctDNA levels predict progression-free survival and anticipate clonal selection.
- Ben O’Leary
- , Sarah Hrebien
- & Nicholas C. Turner
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Article
| Open AccessEngineered nanointerfaces for microfluidic isolation and molecular profiling of tumor-specific extracellular vesicles
Extracellular vesicles can carry many different types of biological cargo and have been investigated as a biomarker for cancer diagnosis. Here the authors develop a microfluidic platform for rapid and sensitive isolation of tumor-specific extracellular vesicles.
- Eduardo Reátegui
- , Kristan E. van der Vos
- & Shannon L. Stott
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Article
| Open AccessPerturbation-response genes reveal signaling footprints in cancer gene expression
Deregulation of signalling is responsible for many cancer phenotypes. Leveraging available perturbation data, here the authors assess large-scale pathway activity patterns based on consensus downstream readout genes, enabling accurate prediction of the effects of mutations and small molecules.
- Michael Schubert
- , Bertram Klinger
- & Julio Saez-Rodriguez
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Article
| Open AccessGenome-wide DNA methylation is predictive of outcome in juvenile myelomonocytic leukemia
Juvenile myelomonocytic leukemia (JMML) is an aggressive disease with limited options for treatment. Here, the authors utilize DNA methylation based subgroups in JMML to predict clinical outcome.
- Elliot Stieglitz
- , Tali Mazor
- & Mignon L. Loh
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Article
| Open AccessAn extracellular matrix-related prognostic and predictive indicator for early-stage non-small cell lung cancer
Prognosis and prediction of adjuvant chemotherapy response in non-small cell lung cancer can have significant clinical impact. Here, the authors show that differential expression of a 29 extracellular matrix gene indicator, EPPI, can predict patient outcome.
- Su Bin LIM
- , Swee Jin TAN
- & Chwee Teck LIM
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Article
| Open AccessA signal-amplifiable biochip quantifies extracellular vesicle-associated RNAs for early cancer detection
Extracellular vesicles (EV)-associated RNAs are serum biomarkers potentially exploitable for early cancer diagnosis. Here the authors develop a catalyzed hairpin DNA circuit within a cationic lipid-polymer hybrid nanoparticle that can detect low–level EV-associated RNAs in early stage cancer patients.
- Jiaming Hu
- , Yan Sheng
- & L. James Lee
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Article
| Open AccessMulti-dimensional genomic analysis of myoepithelial carcinoma identifies prevalent oncogenic gene fusions
Myoepithelial carcinoma (MECA) is a rare aggressive salivary gland cancer. Here, the authors analyze the genomic landscape of MECA and identify a high prevalence of oncogenic gene fusions, primarily PLAG1 fusions, highlighting TGFBR3-PLAG1 as a potential hallmark of MECA.
- Martin G. Dalin
- , Nora Katabi
- & Luc G. T. Morris
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Article
| Open AccessGene isoforms as expression-based biomarkers predictive of drug response in vitro
Altered mRNA splicing features in many cancers, but it has not been linked to drug response. Here, with their meta-analytic framework, the authors analyse pharmacogenomic data to identify isoform-based biomarkers predictive of in vitro drug response, and show them to frequently be strong predictors.
- Zhaleh Safikhani
- , Petr Smirnov
- & Benjamin Haibe-Kains
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Article
| Open AccessGenomic landscape associated with potential response to anti-CTLA-4 treatment in cancers
There is an urgent need to identify predictive markers for selecting responders to immunotherapy. Here, the authors describe a transcriptional predictor of immunotherapy response and assess it in genomic data from ~ 10,000 human tissues across 30 different cancer types.
- Chan-Young Ock
- , Jun-Eul Hwang
- & Ju-Seog Lee
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Article
| Open AccessMitochondrial mutations drive prostate cancer aggression
In prostate cancer, the role of mutations in the maternally-inherited mitochondrial genome are not well known. Here, the authors demonstrate frequent, age-dependent mitochondrial mutation in prostate cancer. Strong links between mitochondrial and nuclear mutational profiles are associated with clinical aggressivity.
- Julia F. Hopkins
- , Veronica Y. Sabelnykova
- & Paul C. Boutros
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Article
| Open AccessSystems analysis of apoptotic priming in ovarian cancer identifies vulnerabilities and predictors of drug response
High-grade serous ovarian cancers (HGS-OvCa) frequently develop chemotherapy resistance. Here, the authors through a systematic analysis of proteomic and drug response data of 14 HGS-OvCa PDXs demonstrate that targeting apoptosis regulators can improve response of these tumors to inhibitors of the PI3K/mTOR pathway.
- Ioannis K. Zervantonakis
- , Claudia Iavarone
- & Joan S. Brugge
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Article
| Open AccessUnraveling a tumor type-specific regulatory core underlying E2F1-mediated epithelial-mesenchymal transition to predict receptor protein signatures
Deregulation of E2F family transcription factors is associated with cancer progression and metastasis. Here, the authors construct a map of the regulatory network around the E2F family, and using gene expression profiles, identify tumour type-specific regulatory cores and receptor expression signatures associated with epithelial-mesenchymal transition in bladder and breast cancer.
- Faiz M. Khan
- , Stephan Marquardt
- & Brigitte M. Pützer
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Article
| Open AccessInsufficient antibody validation challenges oestrogen receptor beta research
A large body of work into the role of oestrogen receptor b (ERb) in breast cancer is contradictory, hindering future progress. Here the authors conduct extensive validation of anti-ERb antibodies , and show that normal and cancerous breast tissue do not express ERb, consistent with RNA-seq data.
- Sandra Andersson
- , Mårten Sundberg
- & Anna Asplund