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| Open AccessCritical role of sphingosine-1-phosphate receptor-2 in the disruption of cerebrovascular integrity in experimental stroke
The sphingolipid sphingosine-1-phosphate (S1P) plays a vital role in vascular homeostasis through the interaction with its receptors S1PR1-5. Here, by using genetic and pharmacological approaches, the authors show that S1PR2-mediated signaling is crucial for the disruption of cerebrovascular integrity and development of intracerebral haemorrhage in a mouse stroke model.
- Gab Seok Kim
- , Li Yang
- & Teresa Sanchez
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Arf6 regulates tumour angiogenesis and growth through HGF-induced endothelial β1 integrin recycling
Targetting tumour angiogenesis is a useful strategy to reduce tumour burden; however, the clinical benefits of anti-angiogenetic drugs are modest. Here, the authors show that HGFR signalling, which contributes to tumour angiogenesis, requires Arf6 and that blocking Arf6 can lead to reduced tumour growth in mice.
- Tsunaki Hongu
- , Yuji Funakoshi
- & Yasunori Kanaho
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| Open AccessQuantitative interactome analysis reveals a chemoresistant edgotype
Changes in protein–protein interactions result in changes to cellular phenotype. Here the authors use crosslinking mass spectrometry to derive a quantitative protein interaction network in drug-sensitive and -resistant HeLa cells, and uncover a chemoresistant ‘edgotype’.
- Juan D. Chavez
- , Devin K. Schweppe
- & James E. Bruce
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The cell cycle regulator 14-3-3σ opposes and reverses cancer metabolic reprogramming
The transcription factor c-Myc is a master regulator of cellular metabolism and has an important role in tumorigenesis. Phanet al. show that 14-3-3σ, an inhibitor of cell cycle progression, also suppresses tumour-promoting metabolic programmes by promoting the degradation of c-Myc.
- Liem Phan
- , Ping-Chieh Chou
- & Mong-Hong Lee
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| Open AccessDNA methylation of oestrogen-regulated enhancers defines endocrine sensitivity in breast cancer
The molecular factors influencing patient response to endocrine therapy are poorly understood. Here Stone et al.characterize the DNA methylome of endocrine response and show that methylation of oestrogen receptor-associated enhancers underpins endocrine sensitivity in human breast cancer.
- Andrew Stone
- , Elena Zotenko
- & Susan J. Clark
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A drug-specific nanocarrier design for efficient anticancer therapy
Telodendrimers are versatile and robust nanoparticle-based drug carriers. From a screen of potential small-molecule building blocks, Shi et al.identify rhein-containing telodendrimers as stable and effective nanocarriers of doxorubicin for treating a xenograft Raji lymphoma model.
- Changying Shi
- , Dandan Guo
- & Juntao Luo
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Clinical implications of genomic alterations in the tumour and circulation of pancreatic cancer patients
Somatic mutations have been reported in pancreatic adenocarcinomas. Here, Sausen et al. identify further mutations and find that mutations in the chromatin modifying gene, MLL, are associated with increased survival, and that the presence of circulating tumour DNA in the serum of patients is associated with poor survival.
- Mark Sausen
- , Jillian Phallen
- & Victor E. Velculescu
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Non-redundant requirement for CXCR3 signalling during tumoricidal T-cell trafficking across tumour vascular checkpoints
Tumours secrete many lymphocyte-attracting chemokines. Here the authors show that despite the abundance of their ligands, CCR2 and CCR5 do not mediate trafficking of effector CD8 T cells into the tumour, whereas CXCR3 is essential for this process and for T-cell-based elimination of melanoma in mice.
- M. E. Mikucki
- , D. T. Fisher
- & S. S. Evans
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A chemogenomic screening identifies CK2 as a target for pro-senescence therapy in PTEN-deficient tumours
It has been proposed that the identification of genes regulating senescence in the absence of PTEN might help develop pro-senescence compounds for the treatment of cancer. Here, the authors use a combination of chemical and shRNA functional screen and identify CK2 as a potential target.
- Madhuri Kalathur
- , Alberto Toso
- & Andrea Alimonti
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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 AccessCdk1 phosphorylates the Rac activator Tiam1 to activate centrosomal Pak and promote mitotic spindle formation
Centrosome separation, promoted by the kinesin Eg5, is antagonized by the guanine nucleotide exchange factor Tiam1 through an unknown mechanism. Here Whalley et al. show that Tiam1 is phosphorylated by cyclin-dependent kinase 1 in prophase, leading to downstream activation of p21-activated kinases (PAKs).
- Helen J. Whalley
- , Andrew P. Porter
- & Angeliki Malliri
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| Open AccessWASH and Tsg101/ALIX-dependent diversion of stress-internalized EGFR from the canonical endocytic pathway
Stress induces ligand-independent endocytosis of EGF receptor (EGFR), but its fate and role in signalling are not known. Here Tomas et al. show that stress-internalized EGFR accumulates and is retained in distinct multivesicular bodies, and delays the onset of stress-induced apoptosis.
- Alejandra Tomas
- , Simon O. Vaughan
- & Clare E. Futter
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Activating MET kinase rearrangements in melanoma and Spitz tumours
Several oncogenic mutations have been identified in melanoma; however, despite exhaustive sequencing, in a subset of melanomas no oncogenic mutation has been identified. Here, the authors identify new genomic rearrangements causing oncogenic fusions between the kinase domain of MET and several N-terminal partners in Spitzoid tumours.
- Iwei Yeh
- , Thomas Botton
- & Boris C. Bastian
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Inhibition of vemurafenib-resistant melanoma by interference with pre-mRNA splicing
BRAF inhibitors have shown encouraging clinical effects in melanoma patients; however, patients rapidly develop resistance via different mechanisms including alternative splicing. Here the authors find a specific mutation affecting BRAF splicing and highlight the therapeutic potential of splicing interference.
- Maayan Salton
- , Wojciech K. Kasprzak
- & Tom Misteli
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| Open AccessChip-based analysis of exosomal mRNA mediating drug resistance in glioblastoma
Predicting and monitoring chemotherapy response remains a challenge for glioma treatment. Here the authors show that a microfluidic device can isolate glioma-derived exosomes from patient blood and accurately determine the levels of mRNA of key enzymes important for chemoresponsiveness.
- Huilin Shao
- , Jaehoon Chung
- & Ralph Weissleder
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The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets
Precision oncology relies on model systems that reflect the genomic heterogeneity of human cancers. Here the authors characterize a panel of 151 colorectal cancer cell lines with respect to genetic mutations, expression profiles and drug sensitivity to identify new therapeutic targets.
- Enzo Medico
- , Mariangela Russo
- & Alberto Bardelli
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| Open AccessThe NOXA–MCL1–BIM axis defines lifespan on extended mitotic arrest
Cells experiencing extended mitotic arrest often undergo cell death as a result of steadily declining levels of the apoptotic inhibitor MCL1, but the mechanism controlling this process is poorly understood. Here, Haschka et al.show that the BH3-only protein NOXA promotes the degradation of MCL1, enabling BIM-dependent cell death.
- Manuel D. Haschka
- , Claudia Soratroi
- & Luca L. Fava
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Galanin modulates the neural niche to favour perineural invasion in head and neck cancer
Perineural invasion occurs in many head and neck cancers and is thought to be an active process where tumour cells degrade the neural sheath. Here the authors show that the neuropeptide galanin mediates the crosstalk between nerves and cancer cells to promote malignant progression.
- Christina Springstead Scanlon
- , Rajat Banerjee
- & Nisha J. D’Silva
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Inhibition of KRAS codon 12 mutants using a novel DNA-alkylating pyrrole–imidazole polyamide conjugate
RAS, identified over 30 years ago as a potent oncogene, is one of the most commonly mutated genes in cancer. Here the authors show that KR12, an alkylating reagent that specifically cleaves the DNA coding for the G12D and G12V activated variants of KRAS, limits the growth of KRAS mutant cells in vitro and in vivo.
- Kiriko Hiraoka
- , Takahiro Inoue
- & Hiroki Nagase
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Amplification of oxidative stress by a dual stimuli-responsive hybrid drug enhances cancer cell death
Cancer cells have elevated levels of reactive oxygen species. Here the authors show that cancer cells can be selectively killed in vitro and in vivoby an oxidative stress-activated drug, which amplifies the generation of reactive oxygen species while blocking the cells’ antioxidant defense.
- Joungyoun Noh
- , Byeongsu Kwon
- & Dongwon Lee
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Targeting matriptase in breast cancer abrogates tumour progression via impairment of stromal-epithelial growth factor signalling
Matriptase, a transmembrane serine protease, has been implicated in breast cancer since its discovery, but the mechanisms of this implication have not been elucidated. Here the authors show that matriptase abrogation in vivoaffects c-Met signalling and the growth of breast cancer cells.
- Gina L. Zoratti
- , Lauren M. Tanabe
- & Karin List
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| Open AccessWhole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets
Diagnosis of pancreatic ductal adenocarcinoma (PDA) has poor long-term survival rates with limited therapy options. Here Witkiewicz et al.use microdissection and whole-exome sequencing to identify novel recurrent PDA mutations, highlighting the genetic diversity of this aggressive cancer.
- Agnieszka K. Witkiewicz
- , Elizabeth A. McMillan
- & Erik S. Knudsen
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The E3 ubiquitin ligase Trim7 mediates c-Jun/AP-1 activation by Ras signalling
Ras signalling activates the transcription factor c-Jun/AP-1, but the mechanism was unclear. Here, Chakraborty et al.describe a phosphorylation–ubiquitination cascade involving MSK1 and the E3 ubiquitin ligases Trim7 and RACO-1, which mediates c-Jun activation in Ras-driven lung tumorigenesis.
- Atanu Chakraborty
- , Markus E. Diefenbacher
- & Axel Behrens
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| Open AccessIL-6-mediated environmental conditioning of defective Th1 differentiation dampens antitumour immune responses in old age
T-cell responses are dysregulated in aged humans and mice, which leads to poor antitumour responses. Here, the authors demonstrate that this phenomenon is at least partially due to an overproduction of IL-6 caused by ageing and its inhibitory effect on Th1 differentiation of tumour-specific CD4 T cells.
- Hirotake Tsukamoto
- , Satoru Senju
- & Yasuharu Nishimura
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Microtubule disruption synergizes with oncolytic virotherapy by inhibiting interferon translation and potentiating bystander killing
Microtubule-destabilizing drugs and oncolytic viruses are two unrelated approaches to battle cancer. Here the authors show that microtubule-destabilizing drugs potentiate the efficiency of oncolytic rhabdoviruses by altering the cytokine production and response of the tumour cells.
- Rozanne Arulanandam
- , Cory Batenchuk
- & Jean-Simon Diallo
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The nuclear translocation of ERK1/2 as an anticancer target
The extracellular signal-regulated kinase 1/2 (ERK1/2) cascade is involved in the induction and maintenance of cancers. Here the authors design an ERK-derived peptide that blocks ERK nuclear import, thus proposing a novel approach to treat tumours with mutational activation of the ERK pathway.
- Alexander Plotnikov
- , Karen Flores
- & Rony Seger
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| Open AccessAinsliadimer A selectively inhibits IKKα/β by covalently binding a conserved cysteine
IKK is a key inducer of NF-κB, and has been targeted by several small molecule drugs. Here the authors show that a natural product from a Chinese medical herb inhibits NF-κB via covalent binding to a unique conserved region of IKK, and efficiently inhibits tumour growth and sepsis in mice.
- Ting Dong
- , Chao Li
- & Xiaoguang Lei
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Attenuation of nonsense-mediated mRNA decay facilitates the response to chemotherapeutics
Nonsense-mediated mRNA decay (NMD) is a pathway that controls endogenous transcript levels and limits the production of aberrant mRNAs. Here the authors show that NMD is attenuated in cells treated with chemotherapeutic compounds through caspase-mediated proteolytic cleavage of UPF1, a key NMD effector.
- Maximilian W. Popp
- & Lynne E. Maquat
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Epsin is required for Dishevelled stability and Wnt signalling activation in colon cancer development
Wnt receptors and the cytoplasmic signalling adaptor, dishevelled (Dvl), are upregulated in cancer and result in elevated canonical Wnt signalling. Here the authors show that the adaptor protein Epsin acts as a chaperone that protects Dvl from degradation thereby contributing to excess Wnt signalling and colon cancer growth.
- Baojun Chang
- , Kandice L. Tessneer
- & Hong Chen
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Housing temperature-induced stress drives therapeutic resistance in murine tumour models through β2-adrenergic receptor activation
Anticancer treatments are tested in mice housed below thermoneutrality which represents chronic cold-stress. Here Eng et al. show that these mice have activated stress responses leading to therapeutic resistance and that inhibiting adrenergic signaling increases efficacy of anticancer therapies.
- Jason W.-L. Eng
- , Chelsey B. Reed
- & Bonnie L. Hylander
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| Open AccessIdentification of FOXM1 as a therapeutic target in B-cell lineage acute lymphoblastic leukaemia
FOXM1, a transcription factor with roles in cell cycle progression, is highly expressed in the majority of solid tumours. Here the authors show that FOXM1 is an ideal therapeutic target in B-cell acute lymphoblastic leukaemia (ALL) due to its dispensability for normal B-cell development.
- Maike Buchner
- , Eugene Park
- & Markus Müschen
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| Open AccessHighly specific in vivo gene delivery for p53-mediated apoptosis and genetic photodynamic therapies of tumour
Alterations of p53 are associated with more than half of all human cancers. Here the authors present a new pH-sensitive nanoparticle that is delivered via systemic circulation and combines gene delivery to restore p53 with expression of Killerred protein to induce photosensitization.
- S.-Ja Tseng
- , Zi-Xian Liao
- & Ivan M. Kempson
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| Open AccessDisruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis
STAT3 is an intracellular transducer of cytokine signals that cooperates with Ras in tumour formation and is often activated in lung cancer. Here the authors show that STAT3 acts as a tumour suppressor in a mouse model of Kras-driven lung adenocarcinoma.
- Beatrice Grabner
- , Daniel Schramek
- & Emilio Casanova
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| Open AccessPredicting clinical response to anticancer drugs using an ex vivo platform that captures tumour heterogeneity
Efficacy of anticancer treatments vary across patients, imposing a need for personalized approaches. Here the authors show that responsiveness to chemotherapy can be predicted using tumour explant cultures in a patient-matched microenvironment, coupled with a machine-learning algorithm.
- Biswanath Majumder
- , Ulaganathan Baraneedharan
- & Pradip K. Majumder
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The cholesterol transporter ABCG1 links cholesterol homeostasis and tumour immunity
ABCG1 transporter pumps cholesterol out of the cell. Here, the authors show that ABCG1-deficient mice have reduced tumour growth due to a switch of the tumour-associated macrophages from a tumour-promoting to tumour-suppressing phenotype, and are protected from the pro-tumorigenic effects of a Western-like diet.
- Duygu Sag
- , Caglar Cekic
- & Catherine C. Hedrick
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| Open AccessMechanism of erosion of nanostructured porous silicon drug carriers in neoplastic tissues
The degradation of materials used in biological applications has an important bearing on their long term performance. Here, the authors show how porous silicon nanoparticle degradation can be accelerated in vivothrough the influence of local tissue pathology, likely influencing drug delivery performance.
- Adi Tzur-Balter
- , Zohar Shatsberg
- & Natalie Artzi
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| Open AccessTemporally sequenced anticancer drugs overcome adaptive resistance by targeting a vulnerable chemotherapy-induced phenotypic transition
Adaptive resistance is an emerging cause of chemotherapy failure in cancer. Here the authors show that adaptive resistance to taxanes is mediated by the upregulation of SFK/Hck survival signalling, and that sequential administration of taxanes and SFK/Hck inhibition restores tumor cell chemosensitivity.
- Aaron Goldman
- , Biswanath Majumder
- & Shiladitya Sengupta
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A leak pathway for luminal protons in endosomes drives oncogenic signalling in glioblastoma
Glioblastoma multiforme is the most common and aggressive form of primary brain tumour, and in 50% of cases EFGR is mutated, amplified or upregulated. Here the authors show that NHE9 controls the amount of EGFR at the membrane surface of brain tumour-initiating stem cells by affecting the luminal pH of sorting endosomes.
- Kalyan C. Kondapalli
- , Jose P. Llongueras
- & Rajini Rao
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Tumour suppressor TRIM33 targets nuclear β-catenin degradation
Aberrant activation of β-catenin in the nucleus has been implicated in several cancers, but the mechanisms regulating nuclear β-catenin are not well understood. Here the authors identify Trim33 as new E3 ligase targeting nuclear β-catenin independently of Wnt signal.
- Jianfei Xue
- , Yaohui Chen
- & Suyun Huang
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| Open AccessAn oncogenic role of Agrin in regulating focal adhesion integrity in hepatocellular carcinoma
The proteoglycan Agrin is known to be expressed in neurons and muscle and to bind ECM protein laminin. Here the authors report that Agrin promotes hepatocellular carcinoma by stimulating proliferation, decreasing focal adhesion, increasing invasiveness and promoting an epithelial-to-mesenchymal transition.
- Sayan Chakraborty
- , Manikandan Lakshmanan
- & Wanjin Hong
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ADAM8 as a drug target in pancreatic cancer
Expression of ADAM8, a metalloprotease disintegrin, correlates with worse prognosis in pancreatic adenocarcinoma (PDAC). Here Schlomann et al. show that ADAM8 promotes PDAC invasiveness, and develop a peptide inhibitor that blocks ADAM8 function and impedes PDAC progression in mouse models.
- Uwe Schlomann
- , Garrit Koller
- & Jörg W. Bartsch
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Intratumoral genome diversity parallels progression and predicts outcome in pediatric cancer
Phenotypic and genetic heterogeneity of cells within a tumour is thought to mediate treatment resistance and contribute to cancer progression. Here the authors show that genetic diversity in pediatric cancers is common after chemotherapy and can be quantified to predict survival.
- Linda Holmquist Mengelbier
- , Jenny Karlsson
- & David Gisselsson
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| Open AccessGd-metallofullerenol nanomaterial as non-toxic breast cancer stem cell-specific inhibitor
A metallofullerenol nanomaterial, Gd@C82(OH)22, was shown to inhibit growth of several solid cancers in preclinical models and yet exhibit low toxicity. Herein the authors show that Gd@C82(OH)22functions as an inhibitor of breast cancer stem cell function via blocking TGF-β and HIF-1α signalling, while sparing normal tissue.
- Ying Liu
- , Chunying Chen
- & Yuliang Zhao
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| Open AccessUCHL1 provides diagnostic and antimetastatic strategies due to its deubiquitinating effect on HIF-1α
When stabilized, HIF-1 can activate adaptation to hypoxia and metastasis. Here the authors show that upregulation of Ubiquitin C-terminal hydrolase-L1 in human cancers promotes metastasis and correlates with poor prognosis because of its role in opposing ubiquitin-mediated degradation of HIF-1.
- Yoko Goto
- , Lihua Zeng
- & Hiroshi Harada
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Massive parallel sequencing uncovers actionable FGFR2–PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma
Intrahepatic cholangiocarcinoma is an aggressive cancer of the bile duct with few treatment options and a below 10% five-year survival rate. Here Sia et al. show a novel FGFR2–PPHLN1 fusion and ARAFmutations that may represent future potential therapeutic targets.
- Daniela Sia
- , Bojan Losic
- & Josep M. Llovet
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Numerical chromosomal instability mediates susceptibility to radiation treatment
Ionizing radiations (IRs) cause widespread genomic damage and can, through unknown mechanisms, lead to changes in chromosome numbers by perturbing the cells undergoing mitosis. Here, the authors investigate the potential mechanism behind the increased susceptibility of mitotic cells to IRs.
- Samuel F. Bakhoum
- , Lilian Kabeche
- & Duane A. Compton
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Clustering of CARMA1 through SH3–GUK domain interactions is required for its activation of NF-κB signalling
Activating mutations in the NF-κB regulator CARMA1 are associated with a form of B-cell lymphoma. Hara et al. show that both physiological and oncogenic CARMA1 signalling can be inhibited by preventing its activation-induced clustering, which is mediated by its SH3 and GUK domains.
- Hiromitsu Hara
- , Tadashi Yokosuka
- & Takashi Saito
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Activating mutations of STAT5B and STAT3 in lymphomas derived from γδ-T or NK cells
NK-cell and γδ-T cell lymphoma share clinic-pathological features; however the driving mutations are largely unknown. Here the authors, using a combination of RNA-Seq analysis, targeted re-sequencing and functional analysis, identify frequent activating mutations in STAT3 and STAT5Bthat may be driver mutations in these diseases.
- Can Küçük
- , Bei Jiang
- & Wing C. Chan
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| Open AccessBCL11A is a triple-negative breast cancer gene with critical functions in stem and progenitor cells
Triple-negative breast cancers (TNBCs) tend to have poor prognosis; however, the mechanisms underlying TNBC pathology are not well understood. Here the authors utilize epidemiologic data and animal models to demonstrate an important role for BCL11A in the genesis and propagation of TNBCs.
- Walid T. Khaled
- , Song Choon Lee
- & Pentao Liu