Featured
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Article
| Open AccessProbabilistic controllability approach to metabolic fluxes in normal and cancer tissues
Metabolic rewiring is a feature of many cancers. Here, the authors combine control theory and flux correlation analysis to study the transition of healthy metabolic networks to cancer states, and find that cancer metabolism is characterized by more streamlined flux distributions.
- Jean-Marc Schwartz
- , Hiroaki Otokuni
- & Jose C. Nacher
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Article
| Open AccessIdentification of metabolic vulnerabilities of receptor tyrosine kinases-driven cancer
Cancer subtypes may have distinct metabolic vulnerabilities that can be exploited for therapeutic interventions. Here, the authors show that in lung cancer, genetic activation of distinct oncogenic receptor tyrosine kinases results in unique metabolic liabilities and, in particular, EGFR aberrant cancers rely on the serine biosynthetic pathway while FGFR aberrant cancers rely on glycolysis.
- Nan Jin
- , Aiwei Bi
- & Min Huang
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Article
| Open AccessRegulating intracellular fate of siRNA by endoplasmic reticulum membrane-decorated hybrid nanoplexes
The silencing efficiency of siRNA delivered by non-viral cationic vectors is limited due to endosomal/lysosomal degradation. Here, the authors develop endoplasmic reticulum-coated vesicles as a biomimetic vector for siRNA delivery and show that they improve inhibition of tumor growth in mice in vivo.
- Chong Qiu
- , Hu-Hu Han
- & Qiang Zhang
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Article
| Open AccessFOXF2 reprograms breast cancer cells into bone metastasis seeds
Bone metastasis in breast cancer patients causes major skeletal-related complications. Here, the authors show that FOXF2/BMP/SMAD pathway plays a major role in bone metastasis and suggest targeting this axis to manage bone metastasis.
- Shuo Wang
- , Gui-Xi Li
- & Yu-Mei Feng
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Article
| Open AccessTargeting enhancer switching overcomes non-genetic drug resistance in acute myeloid leukaemia
There is increasing evidence that epigenetic mechanisms contribute to therapeutic resistance in cancer. Here the authors study AML patient samples and a mouse model of non-genetic resistance and find that transcriptional plasticity drives stable epigenetic resistance, and identify regulators of enhancer function as important modulators of resistance.
- Charles C. Bell
- , Katie A. Fennell
- & Mark A. Dawson
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Article
| Open AccessAdenoviral vaccine targeting multiple neoantigens as strategy to eradicate large tumors combined with checkpoint blockade
Vaccination against neo-antigens has resulted in an effective antitumor response in several models. Here, the authors show that delivery of larger sets of neo-antigens using an adenovirus-based vaccination platform, results in much better tumor protection when combined with checkpoint blockade in a mouse model of advanced disease.
- Anna Morena D’Alise
- , Guido Leoni
- & Elisa Scarselli
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Article
| Open AccessSmall-molecule targeting of MUSASHI RNA-binding activity in acute myeloid leukemia
The RNA binding protein MUSASHI-2 (MSI2) is a potential therapeutic target for acute myeloid leukemia. Here the authors identify a small molecule inhibitor of MSI2 and characterize its effects in a murine leukemia model.
- Gerard Minuesa
- , Steven K. Albanese
- & Michael G. Kharas
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Article
| Open AccessRegulation of CAR T cell-mediated cytokine release syndrome-like toxicity using low molecular weight adapters
Chimeric antigen receptor (CAR) T cell anti-cancer therapies might result in toxic side effects. Here the authors present a strategy based on the modulation of CAR T cells via administration of a bispecific adapter that target them to cancer cells, resulting in diminished CAR-T cells toxicity and enhanced solid tumor eradication.
- Yong Gu Lee
- , Haiyan Chu
- & Philip S. Low
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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 AccessCommunity assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen
Resistance to first line treatment is a major hurdle in cancer treatment, that can be overcome with drug combinations. Here, the authors provide a large drug combination screen across cancer cell lines to benchmark crowdsourced methods and to computationally predict drug synergies.
- Michael P. Menden
- , Dennis Wang
- & Julio Saez-Rodriguez
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Article
| Open AccessNon-proteolytic ubiquitination of Hexokinase 2 by HectH9 controls tumor metabolism and cancer stem cell expansion
Cancer cells develop specific metabolic adaptations. Here, the authors show that in prostate cancer models, the ubiquitin ligase Hect9 promotes tumor growth by accelerating glucose metabolism via ubiquitination of Hexokinase 2, a central regulator of glycolysis.
- Hong-Jen Lee
- , Chien-Feng Li
- & Chia-Hsin Chan
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Article
| Open AccessKRAS-specific inhibition using a DARPin binding to a site in the allosteric lobe
Mutant RAS family members occur in a wide range of tumour types, and there is a great interest in identifying isoform-specific inhibitors. Here, the authors characterise two designed ankyrin repeat proteins (DARPins) that specifically inhibit the KRAS isoform by binding to the region around the KRAS-specific residue histidine 95 and show that they affect KRAS/effector interactions in different ways.
- Nicolas Bery
- , Sandrine Legg
- & Terence H. Rabbitts
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Article
| Open AccessLncRNA-p21 alters the antiandrogen enzalutamide-induced prostate cancer neuroendocrine differentiation via modulating the EZH2/STAT3 signaling
The induction of neuroendocrine differentiation occurs in enzalutamide treated castration resistant prostate cancer. Here, the authors show that lncRNA-21 mediates enzalutamide induced neuroendocrine differentiation through EZH2/STAT axis and EZH2 inhibition suppresses this differentiation.
- Jie Luo
- , Keliang Wang
- & Chawnshang Chang
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Article
| Open AccessA pan-cancer analysis of synonymous mutations
Synonymous mutations do not alter amino acid sequence but may exert oncogenic effects in other ways. Here, the authors present a catalogue of synonymous mutations in cancer and characterise their properties.
- Yogita Sharma
- , Milad Miladi
- & Sven Diederichs
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Article
| Open AccessExploiting interconnected synthetic lethal interactions between PARP inhibition and cancer cell reversible senescence
Senescence induction is known to induce stable proliferation arrest. Here, the authors show that sustained PARP inhibition promotes a reversible p53-independent senescence, and that PARP inhibition is synthetic lethal when combined with senolytic agents in pre-clinical models of ovarian and breast cancer.
- Hubert Fleury
- , Nicolas Malaquin
- & Francis Rodier
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Article
| Open AccessLIF regulates CXCL9 in tumor-associated macrophages and prevents CD8+ T cell tumor-infiltration impairing anti-PD1 therapy
LIF is a pleiotropic cytokine that promotes an immunosuppressive microenvironment and has critical functions in embryonic development. Here, the authors show that LIF regulates CD8+ T cell tumor infiltration in cancer by repressing CXCL19 and promoting the presence of protumoral macrophages and thatLIF inhibition, via neutralizing antibodies, promotes T cell infiltration and synergizes with immune checkpoint inhbitors resulting in tumor regression and immunological memory.
- Mónica Pascual-García
- , Ester Bonfill-Teixidor
- & Joan Seoane
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Article
| Open AccessTumor-associated reactive astrocytes aid the evolution of immunosuppressive environment in glioblastoma
Astrocytes play important roles in neuroinflammatory diseases. Here the authors characterize human glioblastoma-associated astrocytes by gene expression and demonstrate their immunosuppressive role promoted by interactions with tumor and microglia cells in an organotypic model.
- Dieter Henrik Heiland
- , Vidhya M. Ravi
- & Oliver Schnell
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Article
| Open AccessTranslatome analysis reveals altered serine and glycine metabolism in T-cell acute lymphoblastic leukemia cells
The ribosomal protein RPL10 is frequently mutated in T-cell acute lymphoblastic leukemia (T-ALL). Here, the authors show that it promotes proliferation of T-ALL cells by upregulating the serine biosynthesis enzyme phosphoserine phosphatase which in turn modulates serine and glycine metabolism.
- Kim R. Kampen
- , Laura Fancello
- & Kim De Keersmaecker
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Article
| Open AccessSHOC2 phosphatase-dependent RAF dimerization mediates resistance to MEK inhibition in RAS-mutant cancers
Targeted inhibition of the ERK-MAPK pathway is challenged by the development of resistance and toxicity. Here, the authors show that SHOC2 genetic inhibition impairs lung tumour development and improves MEK inhibitor efficacy in RAS- and EGFR-mutant cells.
- Greg G. Jones
- , Isabel Boned del Río
- & Pablo Rodriguez-Viciana
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Article
| Open AccessCordycepin prevents radiation ulcer by inhibiting cell senescence via NRF2 and AMPK in rodents
Radiation damage causes DNA foci to form and senescence, causing ulcers. Here, the authors show that a naturally occurring adenosine analogue, cordycepin, prevents cell senescence via an increase in AMPK/NRF2, so blocking ulcers caused by radiation on skin/intestine/tongue damage in rodents.
- Ziwen Wang
- , Zelin Chen
- & Chunmeng Shi
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Article
| Open AccessCHML promotes liver cancer metastasis by facilitating Rab14 recycle
Metastasis-associated recurrence is a major cause of poor prognosis in hepatocellular carcinoma. Here, the authors show that expression of choroideremia-like (CHML) is elevated and associates with poor prognosis in hepatocellular carcinoma, and mechanistically CHML promotes metastasis in a Rab14-dependent manner.
- Tian-Wei Chen
- , Fen-Fen Yin
- & Dong Xie
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Article
| Open AccessAPC/CCDH1 synchronizes ribose-5-phosphate levels and DNA synthesis to cell cycle progression
Ribose-5-phosphate (R5P) is required for DNA synthesis, but how this is regulated during cell cycle progression is unclear. Here the authors report that the cell cycle regulator APC/C-CDH1 synchronizes cell cycle progression with R5P-derived DNA synthesis by controlling TKTL1 stability
- Yang Li
- , Cui-Fang Yao
- & Jian-Yuan Zhao
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Article
| Open AccessStructural and functional consequences of the STAT5BN642H driver mutation
Hyper-activated STAT5B and its disease-causing variants are of interest as cancer drug targets. Here the authors combine cell based studies, X-ray crystallography, biophysical experiments and MD simulations to structurally and functionally characterize the STAT5BN642H mutant found in aggressive T-cell leukemia and lymphomas and find that it has an increased affinity for self-dimerization.
- Elvin D. de Araujo
- , Fettah Erdogan
- & Patrick T. Gunning
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Article
| Open AccessPRL3-zumab as an immunotherapy to inhibit tumors expressing PRL3 oncoprotein
Phosphatase of regenerating liver 3 (PRL3) is usually found intracellularly, and is over-expressed in cancer cells. Here the authors show that PRL-3 is also detectable on cell surface, and can be recognized by PRL3-zumab to recruit immune cells into tumor to promote anti-tumor immunity, thereby implicating PRL-3 as a potential tumor antigen.
- Min Thura
- , Abdul Qader Al-Aidaroos
- & Qi Zeng
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Article
| Open AccessCaMKK2 in myeloid cells is a key regulator of the immune-suppressive microenvironment in breast cancer
Calcium/calmodulin-dependent kinase kinase 2 (CaMKK2) is highly expressed in several cancers. Here the authors investigate the role of CaMKK2 expression in the tumour microenvironment and show that CaMKK2 expression in tumour-associated macrophages promotes tumour growth by suppressing T cell anti-tumour activity.
- Luigi Racioppi
- , Erik R. Nelson
- & Donald P. McDonnell
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Article
| Open AccessNeuronal differentiation and cell-cycle programs mediate response to BET-bromodomain inhibition in MYC-driven medulloblastoma
BET-bromodomain inhibitors could be used to treat medulloblastoma tumors with Myc amplifications. Here, the authors show that both the response and resistance to BET inhibitors in mice is mediated by bHLH/homeobox transcription factors.
- Pratiti Bandopadhayay
- , Federica Piccioni
- & Rameen Beroukhim
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Article
| Open AccessTumour-associated macrophages exhibit anti-tumoural properties in Sonic Hedgehog medulloblastoma
The Sonic Hedgehog subgroup of medulloblastoma are characterised by the high infiltration of tumour-associated macrophages (TAMs). Here, the authors show that TAM numbers in patients are associated with better prognosis and that, consistently, in a murine model of medulloblastoma, these TAMs have anti-tumoural properties.
- Victor Maximov
- , Zhihong Chen
- & Anna M. Kenney
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Article
| Open AccessLysine 68 acetylation directs MnSOD as a tetrameric detoxification complex versus a monomeric tumor promoter
The molecular mechanism by which acetylation regulates manganese superoxide dismutase (MnSOD) activity and its oncogenicity is unclear. Here the authors show that an acetylation mimicking MnSOD mutant is a monomer, has peroxidase function and acts as a tumor promoting factor.
- Yueming Zhu
- , Xianghui Zou
- & David Gius
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Article
| Open AccessStructures of BCL-2 in complex with venetoclax reveal the molecular basis of resistance mutations
The BCL-2 mutation G101V reduces venetoclax affinity and confers drug resistance in patients with chronic lymphocytic leukaemia. Here, the authors present crystal structures and biochemical analyses of venetoclax bound to BCL-2 and the G101V mutant, revealing the structural basis for venetoclax resistance.
- Richard W. Birkinshaw
- , Jia-nan Gong
- & Peter E. Czabotar
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Article
| Open AccessSialyl Lewisx-P-selectin cascade mediates tumor–mesothelial adhesion in ascitic fluid shear flow
Tumor cell in the peritoneum are often exposed to shear forces generated by ascitic flow during metastasis. Here, the authors show that metastatic cancer stem cells tether more and roll slower than the non-metastatic counterparts, and that sialyl-Lewisx -P-selectin axis mediates peritoneal metastasis.
- Shan-Shan Li
- , Carman K. M. Ip
- & Alice S. T. Wong
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Article
| Open AccessFlexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP
Diagnostic filtering is an important step to analyze the functional and clinical significance of the large number of genetic variants identified from next-generation genome sequencing data. Here, the authors develop a flexible and scalable system for diagnostic filtering of genetic variants using G2P with Ensembl VEP.
- Anja Thormann
- , Mihail Halachev
- & David R. FitzPatrick
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Article
| Open AccessThe oncolytic virus Delta-24-RGD elicits an antitumor effect in pediatric glioma and DIPG mouse models
The oncolytic virus Delta-24-RGD is in clinical trial for adult glioma. Here, the authors show that this virus elicits an immune response in mouse models of pediatric high-grade glioma and diffuse pontine intrinsic glioma, resulting in improved survival.
- Naiara Martínez-Vélez
- , Marc Garcia-Moure
- & Marta M. Alonso
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Article
| Open AccessThe FANCM-BLM-TOP3A-RMI complex suppresses alternative lengthening of telomeres (ALT)
ALT telomeres experience DNA damage that may drive recombination-based telomere elongation. Here, the authors reveal that FANCM plays a critical role in the suppression of ALT activity through its interaction with the BTR (BLM-TOP3A-RMI) complex.
- Robert Lu
- , Julienne J. O’Rourke
- & Hilda A. Pickett
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Article
| Open AccessSORLA regulates endosomal trafficking and oncogenic fitness of HER2
The EGF receptor HER2 is an oncogene protein thought to reside at the plasma membrane, but its endosomal trafficking is currently unclear. Here, the authors report that HER2 is endocytosed and that sortillin-related receptor 1 (SORLA) promotes endosomal HER2 recycling and HER2 oncogenic signalling.
- Mika Pietilä
- , Pranshu Sahgal
- & Johanna Ivaska
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Article
| Open AccessFANCM limits ALT activity by restricting telomeric replication stress induced by deregulated BLM and R-loops
In cancer cells, telomeres can be elongated through homology directed-repair pathways in a process known as Alternative Lengthening of Telomeres (ALT). Here, the authors reveal that FANCM regulates ALT activity and ALT cell proliferation by limiting the activity of uncontrolled BLM and telomeric R-loops.
- Bruno Silva
- , Richard Pentz
- & Claus M. Azzalin
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Article
| Open AccessCollective cell migration and metastases induced by an epithelial-to-mesenchymal transition in Drosophila intestinal tumors
Modelling and visualizing tumor metastasis in Drosophila has been a challenge. Here, the authors show that constitutive expression of Sna in primary adult Drosophila intestinal tumors drives EMT and dissemination of tumor cells, induces collective cell migration and formation of polyclonal metastases.
- Kyra Campbell
- , Fabrizio Rossi
- & Andreu Casali
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Article
| Open AccessTransforming activity of an oncoprotein-encoding circular RNA from human papillomavirus
The authors identify circular RNAs (circRNA) from human papillomavirus and show that circRNA-encoded E7 contributes to cancer cell growth in vitro and in tumor xenografts. Furthermore, circE7 is present in TCGA RNA-Seq data from HPV-positive cancers.
- Jiawei Zhao
- , Eunice E. Lee
- & Richard C. Wang
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Article
| Open AccessA toll-like receptor agonist mimicking microbial signal to generate tumor-suppressive macrophages
Turning tumour promoting macrophages into an anti-tumour phenotype is an attractive therapeutic strategy. Here, the authors develop a polysaccharide-based structure that mimicks pathogen-associated molecular patterns and, by activating the toll-like receptors on macrophage surface, promotes a safe anti-tumour immune response in mouse models.
- Yanxian Feng
- , Ruoyu Mu
- & Chunming Wang
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Article
| Open AccessLNK suppresses interferon signaling in melanoma
LNK is a tumor suppressor in hematopoietic cancers, but its function in melanoma is unclear. Here, the authors show that the overexpression of LNK in melanomas correlate with hyperactive signaling of the RAS-RAF-MEK pathway and LNK enhances melanoma growth and survival and immune evasion by inhibiting IFN signalling.
- Ling-Wen Ding
- , Qiao-Yang Sun
- & H. Phillip Koeffler
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Article
| Open AccessKrt5+/Krt15+ foregut basal progenitors give rise to cyclooxygenase-2-dependent tumours in response to gastric acid stress
Cellular extrinsic environmental factors contribute to tumour development. Here, the authors show that gastric acid stress stimulates tumour formation from a defined tumour-competent Krt5 + /Krt15 + foregut basal progenitor cell population.
- Hyeongsun Moon
- , Jerry Zhu
- & Andrew C. White
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Article
| Open AccessOptimization of 4-1BB antibody for cancer immunotherapy by balancing agonistic strength with FcγR affinity
Agonistic 4-1BB antibodies developed for cancer immunotherapy have suffered from either hepatotoxicity or insufficient anti-cancer activity. Here the authors determine the contribution of FcγR binding and agonistic strength to these outcomes, and engineer a 4-1BB antibody with potent anti-tumor effect and no liver toxicity in mice.
- Xinyue Qi
- , Fanlin Li
- & Xuanming Yang
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Article
| Open AccessMethylation and PTEN activation in dental pulp mesenchymal stem cells promotes osteogenesis and reduces oncogenesis
Mesenchymal stem cells derived from dental pulp (DP-MSCs) differ in oncogenesic and developmental potential compared to those from bone marrow. Here, the authors show that decreased DNA methylation and histone H3K9Me2 enrichment along with higher PTEN activation in DP-MSCs promotes osteogenesis and reduces oncogenesis.
- Wen-Ching Shen
- , Yung-Chih Lai
- & Shih-Chieh Hung
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Article
| Open AccessAlbumin tailoring fluorescence and photothermal conversion effect of near-infrared-II fluorophore with aggregation-induced emission characteristics
There is a balance between the fluorescence and photothermal properties of fluorescent molecules. Here, the authors report on an NIR-II fluorophore which binds with human serum albumin changing the equilibrium, increasing the photothermal efficiency, and demonstrate application of this for tumour ablation.
- Shuai Gao
- , Guoguang Wei
- & Wei Lu
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Article
| Open AccessALPK1 hotspot mutation as a driver of human spiradenoma and spiradenocarcinoma
Spiradenoma and cylindroma are skin adnexal tumors that can behave aggressively and undergo malignant transformation. Here, the authors genetically assess a cohort of these adnexal tumours, highlighting recurrent ALPK1 mutations and revealing the genomic landscape of these rare tumours.
- Mamunur Rashid
- , Michiel van der Horst
- & David J. Adams
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Article
| Open AccessTargeting lonidamine to mitochondria mitigates lung tumorigenesis and brain metastasis
Brain metastases are a major reason for lung cancer mortality. Here, the authors modify lonidamine to target mitochondria, and show its therapeutic efficacy in inhibiting lung cancer brain metastasis by inducing autophagic cell death in cancer cells.
- Gang Cheng
- , Qi Zhang
- & Ming You
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Article
| Open AccessChromatin dysregulation and DNA methylation at transcription start sites associated with transcriptional repression in cancers
In tumours aberrant epigenetic modifications can alter the transcriptional state. Here, the authors identify a common tumour-specific shift to transcriptional repression associated with DNA methylation and chromatin dysregulation at the transcription start site.
- Mizuo Ando
- , Yuki Saito
- & Joseph A. Califano
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Article
| Open AccessA high-throughput screen indicates gemcitabine and JAK inhibitors may be useful for treating pediatric AML
Pediatric AML is traditionally treated with chemotherapy and stem cell transplant but some subsets of patients have a poor response to therapy. Here, the authors perform a high throughput screen and identify several FDA approved drugs that might be useful in treating this disease.
- Christina D. Drenberg
- , Anang Shelat
- & Sharyn D. Baker
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Article
| Open AccessFunctional linkage of gene fusions to cancer cell fitness assessed by pharmacological and CRISPR-Cas9 screening
Gene fusions are observed in many cancers but their link to tumour fitness is largely unknown. Here, transcriptomic analysis combined with pharmacological and CRISPR-Cas9 screening of cancer cell lines was used to evaluate the functional linkage between fusions and tumour fitness.
- Gabriele Picco
- , Elisabeth D. Chen
- & Mathew J. Garnett
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Article
| Open AccessMEK inhibitors activate Wnt signalling and induce stem cell plasticity in colorectal cancer
Wnt signaling is necessary for colorectal cancer tumorigenesis and stem cell maintenance. Here, the authors identify MEK1/2 inhibitors as potent activators of Wnt/β-catenin signalling and show that clinically approved MEK inhibitors inadvertently induce stem cell plasticity in colorectal cancer
- Tianzuo Zhan
- , Giulia Ambrosi
- & Michael Boutros
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