Featured
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| Open AccessACVR1 R206H cooperates with H3.1K27M in promoting diffuse intrinsic pontine glioma pathogenesis
ACVR1 and H3.1K27M mutations co-occur in diffuse intrinsic pontine glioma. Here, the authors generate a mouse model that recapitulates these genetic lesions and show, using genetic and pharmacological approaches, that the bone morphogenetic protein pathway may be a therapeutic target in these tumours.
- Christine M. Hoeman
- , Francisco J. Cordero
- & Oren J. Becher
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Article
| Open AccessComparative oncogenomics identifies combinations of driver genes and drug targets in BRCA1-mutated breast cancer
It is difficult to identify cancer driver genes in cancers, for instance BRCA1 mutated breast cancer, that are characterised by large scale genomic alterations. Here, the authors develop genetically engineered mouse models of BRCA1-deficient breast cancer that allow highthroughput in vivo perturbation of candidate driver genes, validating drivers Myc, Met, Pten and Rb1, and identifying MCL1 as a collaborating driver whose targeting can impact efficacy of PARP inhibition.
- Stefano Annunziato
- , Julian R. de Ruiter
- & Jos Jonkers
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Article
| Open AccessLsd1 as a therapeutic target in Gfi1-activated medulloblastoma
Medulloblastoma is one of the most prevalent malignant brain tumors in children and has very poor prognosis. In this study, the authors show, using a mouse model of medulloblastoma, that Gfi1 promotes tumor growth by recruiting Lsd1, that this interaction inhibits genes involved in neuronal differentiation, and that Lsd1 may be a therapeutic target in Gfi1-activated tumors.
- Catherine Lee
- , Vasilisa A. Rudneva
- & Robert J. Wechsler-Reya
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Article
| Open AccessAge-specific biological and molecular profiling distinguishes paediatric from adult acute myeloid leukaemias
Acute myeloid leukaemia (AML) affects people of all ages. Here, the authors model AML in vivo and demonstrate that the age of the cell of origin impacts leukaemia development and the genetic signature where adult cells of origin give rise exclusively to AML and young cells of origin give rise to myeloid, lymphoid or mixed phenotype acute leukaemia.
- Shahzya Chaudhury
- , Caitríona O’Connor
- & Karen Keeshan
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Article
| Open AccessHysteresis control of epithelial-mesenchymal transition dynamics conveys a distinct program with enhanced metastatic ability
The epithelial-mesenchymal transition (EMT) is a dynamic process that plays important roles in cancer progression and metastasis. Here, the authors characterize a non-linear hysteretic response of E-cadherin repression during TGFβ-induced EMT that is controlled by the strength of the miR-200s/ZEBs negative feedback loop and enhances metastasis.
- Toni Celià-Terrassa
- , Caleb Bastian
- & Yibin Kang
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Article
| Open AccessLongitudinal single-cell RNA sequencing of patient-derived primary cells reveals drug-induced infidelity in stem cell hierarchy
Drug resistance is one of the major causes of cancer-related deaths. Here, the authors using single cell RNA-seq of oral squamous cell carcinoma patient samples pre- and post-cisplatin treatment show that phenotypically homogenous cell populations display cell state plasticity, with poised chromatin marks at mesenchymal genes in epithelial cells, and that the loss of stem factor Sox2 but gain of Sox9 expression (with de novo gain of H3K27ac sites) is associated with drug-induced adaptation.
- Ankur Sharma
- , Elaine Yiqun Cao
- & Ramanuj DasGupta
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Article
| Open AccessH3K9 methyltransferases and demethylases control lung tumor-propagating cells and lung cancer progression
The effects of epigenetic regulators on different tumor cell populations can affect their potential as anticancer targets. In this study, the authors demonstrate that the histone methyltransferase G9a is a suppressor of lung tumor-propagating cells and tumor progression, acting through chromatin modification with MMP10 as one of its targets for metastasis regulation.
- S. P. Rowbotham
- , F. Li
- & C. F. Kim
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Article
| Open AccessRET rearrangements are actionable alterations in breast cancer
Fusions of the gene RET have been described in thyroid and lung cancers. Here, the AUs identify RET gene alterations, including known fusions, novel fusions, and rearrangements in breast cancer (BC) that are involved in the tumorigenic process and show the benefit of RET therapy in a recurrent BC patient carrying the NCOA4-RET fusion.
- Bhavna S. Paratala
- , Jon H. Chung
- & Kim M. Hirshfield
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Article
| Open AccessDefective DNA damage repair leads to frequent catastrophic genomic events in murine and human tumors
Chromothripsis and chromoanasynthesis lead to locally clustered rearrangements affecting one or a few chromosomes, but their impact on cancer development and progression is unclear. Here the authors analyse the role of DNA repair factors in brain tumors by whole-genome sequencing of tumors from mouse models of medulloblastoma or high grade gliomas.
- Manasi Ratnaparkhe
- , John K. L. Wong
- & Aurélie Ernst
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Article
| Open AccessEstablishment and characterization of new tumor xenografts and cancer cell lines from EBV-positive nasopharyngeal carcinoma
The lack of appropriate models restricts pre-clinical research for nasopharyngeal carcinoma (NPC). Here the authors report the development and characterization of NPC patient-derived xenografts (PDXs), and EBV positive NPC cell line from patient tumor, and suggest their potential use in future NPC research.
- Weitao Lin
- , Yim Ling Yip
- & Sai Wah Tsao
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Article
| Open AccessExosomes derived from HIV-1-infected cells promote growth and progression of cancer via HIV TAR RNA
HIV patients have an increased risk of developing non-AIDS-defining cancers but the molecular mechanisms underlying this predisposition are unclear. Here the authors show that exosomes secreted by HIV-infected T cells or isolated from the blood of HIV-positive patients, stimulate oncogenic properties of cancer cells through the activation of ERK1/2 signaling pathway.
- Lechuang Chen
- , Zhimin Feng
- & Ge Jin
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Article
| Open AccessEVI1 overexpression reprograms hematopoiesis via upregulation of Spi1 transcription
Chr3q26 rearrangements cause overexpression of EVI1 and associate with myeloid neoplasms, but the mechanism behind this association is unclear. Here, using a novel mouse model they show that EVI1 causes premalignant myeloid expansion with suppression of other lineages through upregulation of Spi1/PU.1.
- Edward Ayoub
- , Michael P. Wilson
- & Archibald S. Perkins
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Article
| Open AccessClonal dynamics in osteosarcoma defined by RGB marking
Osteosarcoma is a heterogeneous bone tumour with a high mutational rate. Here the authors use an RGB-based single-cell tracking system to track clonal dynamics in a mouse model of osteosarcoma, which their findings indicate follows a neutral evolution model in which different clones simultaneously coexist and propagate.
- Stefano Gambera
- , Ander Abarrategi
- & Javier García-Castro
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Article
| Open AccessSomatic Trp53 mutations differentially drive breast cancer and evolution of metastases
Mutations in TP53 gene are very common in cancer development. Here the authors take advantage of murine models to show that somatic Trp53 mutations differentially drive breast cancer and evolution of metastases.
- Yun Zhang
- , Shunbin Xiong
- & Guillermina Lozano
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Article
| Open AccessAp4 is rate limiting for intestinal tumor formation by controlling the homeostasis of intestinal stem cells
The c-MYC oncoprotein has many targets whose actions are not fully understood including TFAP4/AP4. Here, the authors show in a mouse model of inherited colorectal cancer that deletion of AP4 decreased the frequency of c-MYC-driven intestinal adenomas, and reveal Ap4 as a mediator of adenoma initiation and regulator of colonic and intestinal stem cell and Paneth cell homeostasis.
- Stephanie Jaeckel
- , Markus Kaller
- & Heiko Hermeking
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Article
| Open AccessHypermethylation of gene body CpG islands predicts high dosage of functional oncogenes in liver cancer
Changes in the DNA methylation status are commonly observed in cancer but their impact on cancer development is unclear. Here, combining DNA methylation and expression profiles from a murine model of hepatocellular carcinoma with those from human samples, the authors report an epigenetic reprogramming process ensuring increased dosage of an “oncogene module”.
- Maria Arechederra
- , Fabrice Daian
- & Flavio Maina
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Article
| Open AccessA PDGFRα-driven mouse model of glioblastoma reveals a stathmin1-mediated mechanism of sensitivity to vinblastine
Amplification of PDGFRα is a common alteration in glioblastoma. In this study, the authors develop a genetically engineered mouse model of GBM based on autocrine, chronic stimulation of overexpressed PDGFR and discover Stathmin1 as an important PDGFRα regulated-protein involved in the response to vinstabline.
- Hyun Jung Jun
- , Vicky A. Appleman
- & Al Charest
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Article
| Open AccessOrganoid cultures recapitulate esophageal adenocarcinoma heterogeneity providing a model for clonality studies and precision therapeutics
Esophageal adenocarcinoma (EAC) has a poor 5-year survival rate and lacks robust preclinical models for use in research. Here, the authors show that newly derived organoids recapitulate the transcriptomic, genetic, and morphological landscape of the primary EAC tumors and provide a platform to test drug sensitivity and study tumor clonality.
- Xiaodun Li
- , Hayley E. Francies
- & Mathew J. Garnett
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Article
| Open AccessSubclonal mutation selection in mouse lymphomagenesis identifies known cancer loci and suggests novel candidates
Evidence implicating cancer drivers can be sparse when limited to clonal events. Here, the authors present a retrovirus driven in vivo lymphomagenesis time course including hundreds of thousands of subclonal mutations and demonstrate the utility of these in mapping the selective forces affecting cancer gene loci, including negatively selected mutations.
- Philip Webster
- , Joanna C. Dawes
- & Anthony G. Uren
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Article
| Open AccessPatient derived organoids to model rare prostate cancer phenotypes
There are few available models to study neuroendocrine prostate cancer. Here they develop and characterize patient derived organoids from metastatic lesions, use these models to show the role of EZH2 in driving neuroendocrine phenotype, and perform high throughput organoid screening to identify therapeutic drug combinations.
- Loredana Puca
- , Rohan Bareja
- & Himisha Beltran
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Article
| Open AccessDynamically prognosticating patients with hepatocellular carcinoma through survival paths mapping based on time-series data
Patients with hepatocellular carcinoma require regular follow-up. Here, using Cox-based feature selection to identify key prognostic features, the authors convert time-series follow-up data into a cascading survival map, and show that the approach improves dynamic prognosis prediction for patients.
- Lujun Shen
- , Qi Zeng
- & Peihong Wu
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Article
| Open AccessSETBP1 induces transcription of a network of development genes by acting as an epigenetic hub
SETBP1 variants occur as somatic mutations in several malignancies and as de novo germline mutations in developmental disorders. Here the authors provide evidence that SETBP1 binds to gDNA in AT-rich promoter regions to promote target gene upregulation, indicating SETBP1 functions directly to regulate transcription.
- Rocco Piazza
- , Vera Magistroni
- & Carlo Gambacorti-Passerini
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Article
| Open AccessIn vivo reprogramming drives Kras-induced cancer development
Cellular reprogramming and cancer development share properties. Here, the authors examine the impact of in vivo reprogramming on Kras-induced cancer and show reprogramming-mediated repression of somatic cell enhancers in conjunction with Kras mutation results in rapid PDAC development.
- Hirofumi Shibata
- , Shingo Komura
- & Yasuhiro Yamada
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Article
| Open AccessSomatic genome editing with the RCAS-TVA-CRISPR-Cas9 system for precision tumor modeling
Accurate recapitulation of human disease in animal models requires generation of complex and heterogeneous genetic variation. Here the authors combine RCAS-TVA with CRISPR-Cas9 to generate mouse models of cancer.
- Barbara Oldrini
- , Álvaro Curiel-García
- & Massimo Squatrito
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Article
| Open AccessPeptidomimetic blockade of MYB in acute myeloid leukemia
MYB activity is a key factor for the maintenance of acute myeloid leukemias but it is also a difficult target. Here, the authors develop a peptidomimetic (MYBMIM) that prevents the interaction of the trans-activation domain of MYB with the KIX domain of CBP/P300 and inhibits leukaemia growth.
- Kavitha Ramaswamy
- , Lauren Forbes
- & Alex Kentsis
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Article
| Open AccessMultiplexed in vivo homology-directed repair and tumor barcoding enables parallel quantification of Kras variant oncogenicity
Genome editing technologies enable the rapid interrogation of genetic alterations. Here, the authors present a CRISPR/Cas9-based platform to simultaneously investigate multiple activating point mutations in de novo cancers in mice; and generate panels of Kras-variants in different tissues to induce cancer.
- Ian P. Winters
- , Shin-Heng Chiou
- & Monte M. Winslow
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Article
| Open AccessLoss of PBRM1 rescues VHL dependent replication stress to promote renal carcinogenesis
Mutations in VHL have been linked to clear cell renal cancer, but the molecular mechanisms involved remain unclear. Here the authors generate a mouse model closely mimicking the human disease and show that VHL loss induces DNA replication stress that is rescued by the concomitant loss of PBRM1 permitting transformation.
- Judit Espana-Agusti
- , Anne Warren
- & Athena Matakidou
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Article
| Open AccessAutophagy acts through TRAF3 and RELB to regulate gene expression via antagonism of SMAD proteins
Macroautophagy can regulate cell signalling and tumorigenesis but the molecular mechanisms are unclear. Here the authors show selective degradation of the signalling scaffold TRAF3 by autophagy and consequent activation of the NF-κB family member RELB regulate gene expression via antagonism of SMAD proteins.
- Alice C. Newman
- , Alain J. Kemp
- & Simon Wilkinson
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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 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 AccessClinical responses to adoptive T-cell transfer can be modeled in an autologous immune-humanized mouse model
Combining different types of immune therapies might benefit certain patients. Here, the authors develop an autologous immune-humanized melanoma mouse model that allows the preclinical assessment of cancer cell–T cell interactions from each individual patient and the benefits of immunotherapies combinations.
- Henrik Jespersen
- , Mattias F. Lindberg
- & Jonas A. Nilsson
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Article
| Open AccessPhenotype-driven precision oncology as a guide for clinical decisions one patient at a time
Treatment response in patient-derived models may serve as a biomarker for response in the clinic. Here, the authors use paired patient-derived mouse xenografts and patient-derived primary culture models from head and neck squamous cell carcinomas, including metastasis, as models for high-throughput screening of anti-cancer drugs.
- Shumei Chia
- , Joo-Leng Low
- & Ramanuj DasGupta
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Article
| Open AccessTiming of Smarcb1 and Nf2 inactivation determines schwannoma versus rhabdoid tumor development
SMARCB1 mutations predispose to rhabdoid tumors and schwannomas but the mechanisms underlying the tumor type specificity are unknown. Here the authors present new mouse models and show that early Smarcb1 loss causes rhabdoid tumors whereas loss at later stages combined with Nf2 gene inactivation causes shwannomas.
- Jeremie Vitte
- , Fuying Gao
- & Marco Giovannini
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Article
| Open AccessR-Spondin chromosome rearrangements drive Wnt-dependent tumour initiation and maintenance in the intestine
Recent evidence suggests thatEIF3E–RSPO2 and PTPRK–RSPO3gene fusions promote colorectal cancer. Here, using CRISPR-mediated genome editing, the authors show that endogenous Rspo2 or Rspo3 chromosome rearrangements result in intestinal tumours extremely sensitive to Wnt ligand inhibition.
- Teng Han
- , Emma M. Schatoff
- & Lukas E. Dow
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Article
| Open AccessSomatic chromosomal engineering identifies BCAN-NTRK1 as a potent glioma driver and therapeutic target
The use of mouse models has been an invaluable resource in cancer research but their generation is lengthy and costly. Here the authors describe an approach to generate engineered mouse models carrying specific gene fusions and, as a proof of principle, show that Bcan-Ntrk1 fusion leads to glioblastomas.
- Peter J. Cook
- , Rozario Thomas
- & Andrea Ventura
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Article
| Open AccessGeneration and comparison of CRISPR-Cas9 and Cre-mediated genetically engineered mouse models of sarcoma
Site-specific recombination and CRISPR-Cas9 have been used to generate genetically engineered mouse models of cancer. Here the authors compare sarcomas generated using both systems and see similar genetic and cellular phenotypes, suggesting CRISPR-Cas9 can be used to rapidly generate sarcoma models.
- Jianguo Huang
- , Mark Chen
- & David G. Kirsch
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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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Review Article
| Open AccessModeling the process of human tumorigenesis
A better understanding of the earliest stages of human cancer formation can enable future improvements in early detection, diagnosis and treatment. In this review, the authors summarize the methods enablingde novotumorigenesis protocols to be applied to human cells and the insights derived from them to date, as well as the exciting and relevant technical developments anticipated to extend even further the utility of these strategies.
- Sneha Balani
- , Long V. Nguyen
- & Connie J. Eaves
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Article
| Open AccessReconstituting development of pancreatic intraepithelial neoplasia from primary human pancreas duct cells
Models of human pancreatic intraepithelial neoplasia (PanIN) development do not exist. Here, the authors induce oncogenicKRAS and mutations in CDKN2A, SMAD4 and TP53in primary human pancreatic cells to generate a PanIN model that recapitulates molecular and pathologic features of native PanINs.
- Jonghyeob Lee
- , Emily R. Snyder
- & Seung K. Kim
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Article
| Open AccessMolecular dissection of colorectal cancer in pre-clinical models identifies biomarkers predicting sensitivity to EGFR inhibitors
The heterogeneity of colorectal cancer has important clinical and therapeutic implications. Here the authors analysed the responses of a large biobank of organoids and xenografts derived from colorectal patients to a panel of clinically relevant therapeutic agents to identify genes signatures associated with drug response.
- Moritz Schütte
- , Thomas Risch
- & Marie-Laure Yaspo
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Article
| Open AccessFunctional exploration of colorectal cancer genomes using Drosophila
Colorectal cancers carry multiple mutations. Here, the authors use Drosophilaas a model organism and assess multiple combinations of mutations and their response to various drugs, providing further insight into drug resistance mechanisms.
- Erdem Bangi
- , Claudio Murgia
- & Ross L. Cagan
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Article
| Open AccessClonal dynamics following p53 loss of heterozygosity in Kras-driven cancers
Using mosaic analysis with double markers to label genetically-distinct clones in established tumors, the authors studied the effects of p53 loss in lung and pancreatic cancers. They find that loss of p53 enhances progression in both models but only influences initiation in the pancreas.
- Mandar Deepak Muzumdar
- , Kimberly Judith Dorans
- & Tyler Jacks
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Article
| Open AccessThe tumour suppressor CYLD regulates the p53 DNA damage response
CYLD is a deubiquitinase known to act as a tumour suppressor in different models of carcinogenesis. Here, the authors show that CYLD suppresses carcinogen-induced tumorigenesis by deubiquitinating p53 and promoting its stabilization and activation in response to DNA damage.
- Vanesa Fernández-Majada
- , Patrick-Simon Welz
- & Manolis Pasparakis
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Article
| Open AccessmiR-625-3p regulates oxaliplatin resistance by targeting MAP2K6-p38 signalling in human colorectal adenocarcinoma cells
Oxaliplatin resistance in colorectal cancers is a major clinical problem, and predictive markers are urgently needed. Here, the authors show that miR-625-3pexpression reduces the sensitivity of colorectal cancer cells to oxaliplatin by targeting the kinase MAP2K6, an activator of the MAPK14 pathway.
- Mads Heilskov Rasmussen
- , Iben Lyskjær
- & Claus Lindbjerg Andersen
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Article
| Open AccessEstablishment of human iPSC-based models for the study and targeting of glioma initiating cells
Glioma can originate from the transformation of neural progenitor cells into glioma initiating cells. Here, the authors demonstrate the use of induced pluripotent stem cells as a suitable model for generating neural progenitor cells, which can be subsequently transformed to glioma initiating cells that are able to the generate human glioma-like tumours in mice.
- Ignacio Sancho-Martinez
- , Emmanuel Nivet
- & Juan Carlos Izpisua Belmonte
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Article |
A paclitaxel-loaded recombinant polypeptide nanoparticle outperforms Abraxane in multiple murine cancer models
The encapsulation of a drug into nanoparticles can be a useful way control and improve its efficacy. Here, the authors conjugate paclitaxel to recombinant chimeric polypeptides that self-assemble into therapeutic nanoparticles that outperform Abraxane in murine tumour models.
- Jayanta Bhattacharyya
- , Joseph J. Bellucci
- & Ashutosh Chilkoti
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Article
| Open AccessSomatic CRISPR/Cas9-mediated tumour suppressor disruption enables versatile brain tumour modelling
Gene transfer is a powerful technique to investigate the mechanistic basis of tumorigenesis. Here Zuckermann et al. adapt CRISPR/Cas9 genome editing to target potential oncogenes somatically in vivo, establishing a fast and convenient system for validating novel genetic candidates.
- Marc Zuckermann
- , Volker Hovestadt
- & Jan Gronych