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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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Article
| Open AccessEvaluating cell lines as models for metastatic breast cancer through integrative analysis of genomic data
While cell lines and organoids are extensively used to study cancer, how closely they resemble the disease in patients remains unclear. Here, Liu et al. shed light on this issue by comparing the genomic and transcriptomic profiles of different breast cancer cell lines and organoids to data from patient-derived breast cancer metastases.
- Ke Liu
- , Patrick A. Newbury
- & Bin Chen
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Article
| Open AccessHydro-Seq enables contamination-free high-throughput single-cell RNA-sequencing for circulating tumor cells
Transcriptome analysis of circulating tumor cells (CTCs) provides insights into monitoring target therapeutics and underlying tumor metastasis. Here the authors present Hydro-Seq, a contamination-free high-throughput hydrodynamic scRNA-seq barcoding technique for rare CTCs.
- Yu-Heng Cheng
- , Yu-Chih Chen
- & Euisik Yoon
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Article
| Open AccessAssociation analyses identify 31 new risk loci for colorectal cancer susceptibility
In colorectal cancer (CRC), finding loci associated with risk may give insight into disease aetiology. Here, the authors report a genome-wide association analysis in Europeans of 34,627 CRC cases and 71,379 controls, and find 31 new risk loci and 17 new risk SNPs at previously reported loci.
- Philip J. Law
- , Maria Timofeeva
- & Malcolm G. Dunlop
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Article
| Open AccessJNK1/2 represses Lkb1-deficiency-induced lung squamous cell carcinoma progression
LKB1 is frequently mutated in lung squamous cell carcinomas. Here, the authors show that sole LKB1 depletion is sufficient to drive the development of this cancer, where downstream defective MKK7-JNK1/2 signalling activates the ∆Np63/p63 pathway to induce subsequent epithelial cells transformation and tumour progression.
- Jian Liu
- , Tianyuan Wang
- & Francesco J. DeMayo
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Article
| Open AccessNucleoporin Nup155 is part of the p53 network in liver cancer
The nuclear pore complex (NPC) is known to regulate p53 signaling and this has mainly been linked to peripheral NPC subunits. Here the authors show that Nup155 from the NPC inner ring regulates the p53 pathway by controlling p21 translation while also being a target of p53-mediated repression.
- Kerstin Holzer
- , Alessandro Ori
- & Stephan Singer
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Article
| Open AccessCollagen-rich airway smooth muscle cells are a metastatic niche for tumor colonization in the lung
Collagen is a dynamic component of both the tumor and metastatic niche. Here, the authors show that airway smooth muscle cells are a collagen III rich niche bladder cancer cells expressing CD167a, and Stat3 is a downstream target for abrogating these collagen III/CD167a-driven metastatic foci.
- Yu-Cheng Lee
- , Antonina V. Kurtova
- & Keith Syson Chan
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Article
| Open AccessAn integrated stress response via PKR suppresses HER2+ cancers and improves trastuzumab therapy
The HER2 monoclonal antibody, Trastuzumab, is the current standard treatment for HER2+ cancers but resistance to therapy occurs. Here, the authors show that activation of the PKR/eIF2α-P pathway exhibits anti-tumor effects in HER2+ cancer and is required for the response to Trastuzumab.
- Cedric Darini
- , Nour Ghaddar
- & Antonis E. Koromilas
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Article
| Open AccessPFA ependymoma-associated protein EZHIP inhibits PRC2 activity through a H3 K27M-like mechanism
PFA tumours express high levels of EZHIP (also known as CXORF67). Here the authors find that EZHIP directly interacts with the active site of EZH2 and is a competitive inhibitor of PRC2 and that EZHIP gives rise to H3K27me3 genomic profile similar to the K27M oncohistone.
- Siddhant U. Jain
- , Truman J. Do
- & Peter W. Lewis
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Article
| Open AccessSREBP1 drives Keratin-80-dependent cytoskeletal changes and invasive behavior in endocrine-resistant ERα breast cancer
ERα breast cancer can relapse to metastatic disease following endocrine therapy. Here, the authors find that when aromatase inhibitor treatment resistance develops, epigenomic reprogramming drives Keratin-80 upregulation via SREBP1, and promotes cytoskeletal rearrangements that drive cancer cell invasion.
- Ylenia Perone
- , Aaron J. Farrugia
- & Luca Magnani
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Article
| Open AccessRibosome biogenesis during cell cycle arrest fuels EMT in development and disease
Ribosomal DNA transcription is essential for cell growth and division. Here, the authors show that EMT is accompanied by Snail binding to rDNA operons and Rictor association with nucleoli to fuel an induction of ribosome biogenesis during G1/S cell cycle arrest and inhibition of ribosome biogenesis hampers EMT, differentiates primary tumors and reduces metastasis.
- Varsha Prakash
- , Brittany B. Carson
- & C. Theresa Vincent
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Article
| Open AccessSynthetic TRuC receptors engaging the complete T cell receptor for potent anti-tumor response
Supraphysiological T cell activation by chimeric antigen receptor (CAR) contributes to T cell exhaustion and adverse events in CAR T cell therapies. Here the authors engineer a synthetic antigen receptor that integrates into the endogenous TCR complex, preserving natural regulatory circuits and achieving improved performance in mouse tumor models.
- Patrick A. Baeuerle
- , Jian Ding
- & Robert Hofmeister
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Article
| Open AccessRETRACTED ARTICLE: RNA m6A methylation regulates the epithelial mesenchymal transition of cancer cells and translation of Snail
RNA m6A methylation is known to be dysregulated in many cancers. Here, the authors show that m6A methylation of Snail mRNA regulates its translation with potential effects on epithelial mesenchymal transition.
- Xinyao Lin
- , Guoshi Chai
- & Hongsheng Wang
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Article
| Open AccessThe transcription factor CBFB suppresses breast cancer through orchestrating translation and transcription
CBFB is highly mutated in breast cancers and is known to interact with RUNX proteins to regulate transcription. Here, the authors describe a non-canonical role of CBFB in translation regulation in which it binds to mRNAs through hnRNPK, facilitating translation by eIF4B.
- Navdeep Malik
- , Hualong Yan
- & Jing Huang
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