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| Open AccessSOD3 improves the tumor response to chemotherapy by stabilizing endothelial HIF-2α
Tumour vasculature influences drug delivery. Here, the authors show that SOD3 re-expression enhances doxorubicin delivery and effects through normalization of tumour vasculature via the HIF-2a/VE-cadherin pathway.
- Emilia Mira
- , Lorena Carmona-Rodríguez
- & Santos Mañes
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Article
| Open AccessTranscriptomic alterations during ageing reflect the shift from cancer to degenerative diseases in the elderly
Ageing is associated with a pronounced shift in mortality from cancer to degenerative diseases. Here, the authors show that in concordance with this shift, conserved transcriptional alterations during ageing across four vertebrates align with degenerative diseases but are opposite to those in cancer.
- Peer Aramillo Irizar
- , Sascha Schäuble
- & Christoph Kaleta
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Article
| Open Access∆133p53 isoform promotes tumour invasion and metastasis via interleukin-6 activation of JAK-STAT and RhoA-ROCK signalling
Aberrant expression of the Δ133p53 isoform is linked to many cancers. Here, the authors utilise a model of the Δ133p53 isoform that is prone to tumours and inflammation, showing that Δ133p53 promotes tumour cell invasion by activation of the JAK-STAT and RhoA-ROCK pathways in an IL-6 dependent manner.
- Hamish Campbell
- , Nicholas Fleming
- & Antony W. Braithwaite
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Article
| Open AccessDNA methyltransferase inhibition upregulates MHC-I to potentiate cytotoxic T lymphocyte responses in breast cancer
Immunotherapy often fails as a single option treatment in cancer. Here, the authors show that targeting of DNA methyltransferases, such as DNMT1, can potentiate anti-tumor immunity and response to checkpoint inhibition by increasing MHC gene expression and the recruitment of CD8+ T cells.
- Na Luo
- , Mellissa J. Nixon
- & Justin M. Balko
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Article
| Open AccessTumor-derived exosomal miR-1247-3p induces cancer-associated fibroblast activation to foster lung metastasis of liver cancer
How tumor cells control metastatic niche formation is not fully understood. Here, the authors show in a lung metastatic niche, high-metastatic hepatocellular carcinoma cells secrete exosomal miR-1247-3p that leads to activation of β1-integrin-NF-κBsignalling, converting fibroblasts to cancer-associated fibroblasts.
- Tian Fang
- , Hongwei Lv
- & Hongyang Wang
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Article
| Open AccessTNFα blockade overcomes resistance to anti-PD-1 in experimental melanoma
Most melanoma patients do not respond to anti-PD1 therapy. Here, the authors show that TNFα blockade synergizes with anti-PD-1 by preventing anti-PD-1-induced CD8+ T cell death and TIM-3 expression on such cells.
- Florie Bertrand
- , Anne Montfort
- & Bruno Ségui
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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 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 AccessDendrogenin A drives LXR to trigger lethal autophagy in cancers
Dendrogenin A, cholesterol metabolite, has tumor suppressive properties but the mechanisms are unknown. Here the authors show that Dendrogenin A can induce autophagy-mediated cell death in both melanoma and acute myeloid leukaemia.
- Gregory Segala
- , Marion David
- & Sandrine Silvente-Poirot
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Article
| Open AccessExpressed fusion gene landscape and its impact in multiple myeloma
Multiple myeloma is a malignancy of plasma cells in the blood. Here, the authors establish the landscape of fusion genes within this disease, identifying novel recurrent fusion genes that impact survival and may drive disease progression.
- A. Cleynen
- , R. Szalat
- & H. Avet-Loiseau
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Article
| Open AccessGenome-wide association study of classical Hodgkin lymphoma identifies key regulators of disease susceptibility
Classical Hodgkin lymphoma is a cancer that originates in lymph nodes. Little is known about its genetic susceptibility. Here, the authors combined existing and new genome-wide association studies to identify risk loci for classical Hodgkin lymphoma at 6q22.33, and nodular sclerosis Hodgkin lymphoma at 3q28, 6q23.3, 10p14, 13q34, 16p13.13.
- Amit Sud
- , Hauke Thomsen
- & Richard S. Houlston
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Article
| Open AccessStem cell senescence drives age-attenuated induction of pituitary tumours in mouse models of paediatric craniopharyngioma
Senescent cells can promote tumour progression through the activation of a senescenceassociated secretory phenotype (SASP). Here, the authors show that SASP activation is associated with non-cell autonomous cell transformation and tumour initiation in an in vivo model of adamantinomatous craniopharyngioma.
- Jose Mario Gonzalez-Meljem
- , Scott Haston
- & Juan Pedro Martinez-Barbera
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Article
| Open AccessOncogenic PIK3CA induces centrosome amplification and tolerance to genome doubling
Activated PI3K causes cancer, but the role of active PI3K mutations in early stages of malignancy are unclear. Here, the authors show in a mouse model that active PI3K induces centrosome amplification via AKT, ROCK, CDK2/Cyclin E and nucleophosmin, and increased tolerance of genome doubling.
- Inma M. Berenjeno
- , Roberto Piñeiro
- & Bart Vanhaesebroeck
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Article
| Open AccessNSD1- and NSD2-damaging mutations define a subset of laryngeal tumors with favorable prognosis
The authors use an integrative clustering approach to identify two laryngeal cancer clusters with distinct prognosis and show that mutations damaging the NSD1 and NSD2 methyltransferases segregate to the cluster with favorable prognosis, and independently predict longer survival in patients with laryngeal, but not other head and neck cancers.
- Suraj Peri
- , Evgeny Izumchenko
- & Erica A. Golemis
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Article
| Open AccessThe role of CXCR3/LRP1 cross-talk in the invasion of primary brain tumors
The chemokine receptor CXCR3-A is expressed in high grade glioma. Here the authors show that CXCR3-A interacts with LPR1, a protein highly expressed in glioma, and this interaction regulates the trafficking of the receptor ultimately impacting on tumour cell migration.
- Kevin Boyé
- , Nadège Pujol
- & Clotilde Billottet
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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 AccessFbxo4-mediated degradation of Fxr1 suppresses tumorigenesis in head and neck squamous cell carcinoma
Fbxo4 tumour suppressor is part of a SCF E3 ligase which has two known substrates. Here, the authors identify Fxr1 as a substrate of SCFFbxo4 and identify an inherent regulatory feedback loop in head and neck squamous cell carcinoma that results in the bypass of senescence and neoplastic progression.
- Shuo Qie
- , Mrinmoyee Majumder
- & J. Alan Diehl
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Article
| Open AccessPTEN is a protein phosphatase that targets active PTK6 and inhibits PTK6 oncogenic signaling in prostate cancer
PTEN is often lost in prostate cancer. In this study, the authors show that PTEN can act as a protein phosphatase that targets active PTK6, thereby regulating its oncogenic signaling in prostate cancer progression.
- Darren J. Wozniak
- , Andre Kajdacsy-Balla
- & Angela L. Tyner
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Article
| Open AccessEvidence of renal angiomyolipoma neoplastic stem cells arising from renal epithelial cells
Renal angiomyolipomas (AML) contain a mix of clonal tumour cells. Here, through reverse tumour engineering experiments, mouse genetics and analyses of human AML tumours, the authors provide evidence that these mesenchymal tumours originate from renal proximal tubule epithelial cells.
- Ana Filipa Gonçalves
- , Mojca Adlesic
- & Ian J. Frew
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Article
| Open AccessTRIM24 is an oncogenic transcriptional co-activator of STAT3 in glioblastoma
EGF receptor (EGFR) amplification and mutation are major drivers in glioma tumorigenesis but this mechanism is not well understood. Here, the authors show EGFR-upregulated H3K23ac binds TRIM24 which recruits STAT3, leading to activation of STAT3 signaling, enhancing EGFR-driven tumorigenesis.
- Deguan Lv
- , Yanxin Li
- & Haizhong Feng
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Article
| Open AccessMulticolor lineage tracing reveals clonal architecture and dynamics in colon cancer
The clonal architecture of colon cancer and the relevance of tumor cell subpopulations for clonal outgrowth are poorly understood. Here, the authors describe the clonal architecture and dynamics in human colon cancer by using a multicolor lineage tracing approach in colon cancer xenografts.
- Sebastian Lamprecht
- , Eva Marina Schmidt
- & David Horst
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Article
| Open AccessRe-designing Interleukin-12 to enhance its safety and potential as an anti-tumor immunotherapeutic agent
Interleukin-12 (IL-12) is a potent immunotherapeutic agent.
- Pengju Wang
- , Xiaozhu Li
- & Yaohe Wang
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Article
| Open AccessPrevalence and detection of low-allele-fraction variants in clinical cancer samples
High-throughput sequencing is used to identify somatic variants in cancer patients. Here, the authors perform panel-based profiling of 5095 clinical samples and demonstrate that many clinically-actionable variants have low variant allele fractions, requiring assays with high detection sensitivity.
- Hyun-Tae Shin
- , Yoon-La Choi
- & Woong-Yang Park
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| Open AccessScalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors
Identifying the mutational landscape of tumours from cell-free DNA in the blood could help diagnostics in cancer. Here, the authors present ichorCNA, software that quantifies tumour content in cell free DNA, and they demonstrate that cell-free DNA whole-exome sequencing is concordant with metastatic tumour whole-exome sequencing.
- Viktor A. Adalsteinsson
- , Gavin Ha
- & Matthew Meyerson
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Article
| Open AccessSortilin limits EGFR signaling by promoting its internalization in lung cancer
Disruptions in epidermal growth factor receptor (EGFR) trafficking has been linked to tumor progression. Here the authors show that sortilin limits cell proliferation and tumor growth by promoting EGFR internalization.
- Hussein Al-Akhrass
- , Thomas Naves
- & Fabrice Lalloué
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Article
| Open AccessInequality in genetic cancer risk suggests bad genes rather than bad luck
Cancer heritability estimates can be obtained via decomposing trait variance into genetic and other factors. Here, the authors obtain the distribution of absolute genetic risk for 15 common cancers, and they use a number of metrics to show that the genetic risk varies considerably across individuals.
- Mats Julius Stensrud
- & Morten Valberg
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Article
| Open AccessInduction of synthetic lethality in IDH1-mutated gliomas through inhibition of Bcl-xL
Glioblastoma (GBM) cells are often characterized by the presence of the IDH1 R132H mutation and high expression of anti-apoptotic proteins. Here, the authors show that the inhibition of Bcl-xL is synthetically lethal in IDH1-mutated GBM models and that this effect is mediated by the oncometabolite, 2-HG, which reduces Mcl-1 protein levels.
- Georg Karpel-Massler
- , Chiaki Tsuge Ishida
- & Markus D. Siegelin
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Article
| Open AccessAndrogen receptor increases hematogenous metastasis yet decreases lymphatic metastasis of renal cell carcinoma
The incidence of renal cell carcinoma is higher in males than in females due to the different androgen receptor signaling but the molecular mechanisms behind this gender bias are unclear. Here the authors show how androgen receptor expression influences the metastatic route through the regulation of miR-185 and VEGF isoforms.
- Qingbo Huang
- , Yin Sun
- & Chawnshang Chang
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Article
| Open AccessTristetraprolin inhibits macrophage IL-27-induced activation of antitumour cytotoxic T cell responses
IL-27 is one of a number of cytokines that can induce antitumour CD8+ T cell responses. Here the authors show that TTP, encoded by Zfp36, degrades p28 to inhibit IL-27 production by macrophages and is thereby a negative regulator of the antitumour response.
- Qinghong Wang
- , Huan Ning
- & Jianguo Liu
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Article
| Open AccessFrequent miRNA-convergent fusion gene events in breast cancer
Fusion gene research traditionally focuses on fusions that result in hybrid proteins or promoter switching events. Here, the authors demonstrate enrichment of fusions in miRNA host genes in breast cancer, highlighting that disparate fusions could have convergent impact on miRNA.
- Helena Persson
- , Rolf Søkilde
- & Carlos Rovira
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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 AccessCombined activation of MAP kinase pathway and β-catenin signaling cause deep penetrating nevi
Deep penetrating nevi (DPN) are unusual melanocytic neoplasms with unknown genetic drivers. Here the authors show that majority of DPN harbor activating mutations in the β-catenin and the MAP-kinase pathways; this characteristic can help in the classification and grading of these distinctive neoplasms.
- Iwei Yeh
- , Ursula E. Lang
- & Arnaud de la Fouchardière
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Article
| Open AccessThe non-canonical poly(A) polymerase FAM46C acts as an onco-suppressor in multiple myeloma
FAM46C is one of the most frequently mutated genes in multiple myeloma (MM), but its molecular function remains unknown. Here the authors show that FAM46C is a poly(A) polymerase and that loss of function of FAM46C drives multiple myeloma through the destabilisation of ER response transcripts.
- Seweryn Mroczek
- , Justyna Chlebowska
- & Andrzej Dziembowski
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Article
| Open AccessAPOBEC3A is an oral cancer prognostic biomarker in Taiwanese carriers of an APOBEC deletion polymorphism
Oral squamous cell carcinoma is a prevalent malignancy in Taiwan. Here, the authors show that OSCC in Taiwanese show a frequent deletion polymorphism in the cytidine deaminases gene cluster APOBEC3 resulting in increased expression of A3A, which is shown to be of clinical prognostic relevance.
- Ting-Wen Chen
- , Chi-Ching Lee
- & Yu-Sun Chang
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Article
| Open AccessConvergent Akt activation drives acquired EGFR inhibitor resistance in lung cancer
EGFR-mutant non-small cell lung cancer are often resistant to EGFR tyrosine kinase inhibitor treatment. In this study, the authors show that resistant tumors display high Akt activation and that a combined treatment with AKT inhibitors causes synergistic tumour growth inhibition in vitro and in vivo.
- Kirstine Jacobsen
- , Jordi Bertran-Alamillo
- & Rafael Rosell
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Article
| Open AccessStromal and epithelial transcriptional map of initiation progression and metastatic potential of human prostate cancer
Stromal cells contribute to tumor development but the mechanisms regulating this process are still unclear. Here the authors analyze gene expression profiles in the prostate and show that stromal gene signature changes ahead of the epithelial gene signature as prostate cancer initiates and progresses.
- Svitlana Tyekucheva
- , Michaela Bowden
- & Massimo Loda
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Article
| Open AccessSynthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer
Tumours with homologous recombination (HR) defects become sensitive to PARPi. Here, the authors show that androgen receptor (AR) regulates HR and AR inhibition activates the PARP pathway in vivo, thus inhibition of both AR and PARP is required for effective treatment of high risk prostate cancer.
- Mohammad Asim
- , Firas Tarish
- & Thomas Helleday
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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 AccessSIRT7 antagonizes TGF-β signaling and inhibits breast cancer metastasis
Metastatic disease is the major reason for breast cancer-related deaths; therefore, a better understanding of this process and its players is needed. Here the authors report the role of SIRT7 in inhibiting SMAD4-mediated breast cancer metastasis providing a possible therapeutic avenue.
- Xiaolong Tang
- , Lei Shi
- & Baohua Liu
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Article
| Open AccessPericyte-expressed Tie2 controls angiogenesis and vessel maturation
The angiopoietins regulate vascular maturation, angiogenesis and lymphangiogenesis via their Tie receptors that were long believed to be endothelium-specific. Here the authors show that angiopoietins activate and control pericyte function through pericyte-expressed Tie2 triggering of Calpain, Akt and FOXO3A signalling cascades.
- Martin Teichert
- , Laura Milde
- & Hellmut G. Augustin
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Article
| Open AccessDisruption of the C/EBPα—miR-182 balance impairs granulocytic differentiation
C/EBPα is a critical transcription factor involved in myelopoiesis and its inactivation is associated with acute myeloid leukemia (AML). Here the authors show a negative feedback loop between C/EBPα and miR-182 and identify this miRNA as a marker of high-risk AML.
- Alexander Arthur Wurm
- , Polina Zjablovskaja
- & Gerhard Behre
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Article
| Open AccessAttenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis
The vast majority of BRCA1-driven breast cancers derive from luminal progenitor cells but the mechanisms of this lineage specificity are unclear. Here the authors show that dangerous accumulation of DNA-RNA hybrid structures due to RNA polymerase II pausing, occurs specifically in luminal epithelial cells.
- Xiaowen Zhang
- , Huai-Chin Chiang
- & Rong Li
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Article
| Open AccessHypoxia-induced mobilization of NHE6 to the plasma membrane triggers endosome hyperacidification and chemoresistance
Sodium/proton exchangers (NHEs) are critical regulators of pH within the cell and the extracellular microenvironment. Here, the authors show that hypoxia induces mobilization of NHE6 from endosomal compartment to the plasma membrane in a PKC-dependent manner inducing hyper acidification of endosomes and drug resistance.
- Fabrice Lucien
- , Pierre-Paul Pelletier
- & Claire M. Dubois
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Article
| Open AccessVHL deficiency augments anthracycline sensitivity of clear cell renal cell carcinomas by down-regulating ALDH2
The VHL tumour suppressor gene is lost in approximately 70% of clear cell renal cell carcinoma (ccRCC). In this study, the authors demonstrate that VHL loss in these tumours augments anthracyclines chemotherapy by down-regulation of ALDH2.
- Yao-Hui Gao
- , Zhao-Xia Wu
- & Li-Shun Wang
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Article
| Open AccessMYC activation cooperates with Vhl and Ink4a/Arf loss to induce clear cell renal cell carcinoma
Renal cell carcinoma (RCC) is a common and aggressive malignancy. Here, the authors generate two mouse models of the most common RCC subtypes: the human papillary RCC throughMYC activation and clear cell RCC through MYC activation combined with Vhl and Cdkn2adeletion.
- Sean T. Bailey
- , Aleisha M. Smith
- & William Y. Kim
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Article
| Open AccessReplicating viral vector platform exploits alarmin signals for potent CD8+ T cell-mediated tumour immunotherapy
Viruses trigger potent cytotoxic T cell responses, whereas anti-tumour immunity has been difficult to establish. Here the authors engineer a replicating viral delivery system for tumour-associated antigens, which induces alarmin release, innate activation and protective anti-tumour immunity in mice.
- Sandra M. Kallert
- , Stephanie Darbre
- & Daniel D. Pinschewer
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Article
| Open AccessCis-perturbation of cancer drivers by the HTLV-1/BLV proviruses is an early determinant of leukemogenesis
Human T-cell leukaemia virus type-1 and bovine leukaemia virus infect T and B lymphocytes and lead to aggressive leukaemia. Here, the authors show these proviruses integrate near cancer drivers perturbing transcription termination or antisense RNA-dependent interaction, suggesting post-transcriptional mechanisms in some cases.
- Nicolas Rosewick
- , Keith Durkin
- & Anne Van den Broeke
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Article
| Open AccessPTEN regulates glioblastoma oncogenesis through chromatin-associated complexes of DAXX and histone H3.3
PTEN mutations are frequent in glioblastoma and often are associated with therapeutic resistance. Here, the authors demonstrate that PTEN regulates gene expression at the chromatin level by interacting with the histone chaperone DAXX and H3.3, and that DAXX inhibition inhibits PTEN-deficient GBM growth in vivo.
- Jorge A. Benitez
- , Jianhui Ma
- & Frank B. Furnari
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Article
| Open AccessProline metabolism supports metastasis formation and could be inhibited to selectively target metastasizing cancer cells
Metastasizing cancer cells rewire their metabolism to support their malignant phenotypes. Here, the authors show that the acquisition of a metastatic phenotype in breast cancer cell lines results in increased proline catabolism and that inhibition of this pathway decreases lung metastasis formation in two mouse models.
- Ilaria Elia
- , Dorien Broekaert
- & Sarah-Maria Fendt