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SOX2 is a cancer-specific regulator of tumour initiating potential in cutaneous squamous cell carcinoma
The mechanisms that sustain the self-renewal and expansion of cancer cells with tumour initiating potential are not completely understood. Here the authors show that the transcription factor, Sox2, marks tumour initiating cells in cutaneous squamous cell carcinomas and is required for their expansion.
- Jasmin M. Siegle
- , Alice Basin
- & Markus Schober
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Helicobacter pylori CagA promotes Snail-mediated epithelial–mesenchymal transition by reducing GSK-3 activity
Gastric cancer is associated with H. pylori infection and these tumours frequently show features of epithelial–mesenchymal transition (EMT). Here, the authors show that the H. pylorivirulence protein, CagA, reduces the activity of GSK3b, which leads to the stabilization of Snail, a protein that induces EMT.
- Da-Gyum Lee
- , Hyun Sil Kim
- & Yong Chan Lee
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Increased Notch signalling inhibits anoikis and stimulates proliferation of prostate luminal epithelial cells
Prostate epithelia contain basal, luminal and neuroendocrine cells. Here the authors show that overexpression of the Notch intracellular domain in the mouse prostate promotes proliferation and suppresses anoikis of prostate luminal epithelial cells.
- Oh-Joon Kwon
- , Joseph M. Valdez
- & Li Xin
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Structural basis for Smoothened receptor modulation and chemoresistance to anticancer drugs
Antagonists of Smoothened, a class F GPCR involved in the hedgehog pathway, have been developed to treat some cancers. Here Wang et al.report structures of Smoothened in complex with antagonists and an agonist, and describe how mutations may result in resistance to anti-Smoothened treatment.
- Chong Wang
- , Huixian Wu
- & Raymond C. Stevens
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Nanoscale chromatin profiling of gastric adenocarcinoma reveals cancer-associated cryptic promoters and somatically acquired regulatory elements
Epigenetic alterations alter chromatin structure and gene expression and are known contributors to cancer development. Here, Muratani et al.profile multiple epigenetic chromatin marks in primary gastric cancers and identify hundreds of altered promoters and enhancers that drive the gene expression program in these malignancies.
- Masafumi Muratani
- , Niantao Deng
- & Patrick Tan
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| Open AccessThe Opisthorchis viverrini genome provides insights into life in the bile duct
The Asian liver fluke is a parasitic worm that is linked to an increased risk of malignant cancer. Here, the authors sequence the draft genome and transcriptome of this fluke and provide insight into how the species has adapted to be able to survive in the bile duct.
- Neil D. Young
- , Niranjan Nagarajan
- & Robin B. Gasser
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The Pan-Cancer analysis of pseudogene expression reveals biologically and clinically relevant tumour subtypes
The contribution of expressed pseudogenes to cancer pathogenesis is unclear. In this study, Han et al.analyse RNA-seq data from The Cancer Genome Atlas and demonstrate the potential of pseudogenes for investigating cancer mechanisms and discovering prognostic biomarkers.
- Leng Han
- , Yuan Yuan
- & Han Liang
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Lineage-restricted function of the pluripotency factor NANOG in stratified epithelia
The transcription factor Nanog regulates self-renewal in pluripotent stem cells and cancer stem cells. Here the authors show that Nanog is expressed in mouse adult stratified epithelia, and its overexpression increases proliferation and aneuploidy and activates pathways associated to mitosis.
- Daniela Piazzolla
- , Adelaida R. Palla
- & Manuel Serrano
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Legumain protease-activated TAT-liposome cargo for targeting tumours and their microenvironment
Legumain is a protease found expressed in tumour cells and may be useful in the specific targeting of chemotherapeutics to tumour cells. Here, the authors design nanoparticles that are loaded with doxorubicin and contain a legumain cleavage site; once the nanoparticles enter tumour cells legumain activity results in the release of doxorubicin.
- Ze Liu
- , Min Xiong
- & Rong Xiang
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Diverse matrix metalloproteinase functions regulate cancer amoeboid migration
Migrating cancer cells are round or elongated, and it is thought that the differently shaped cells invade surrounding tissue using different mechanisms. Here, Orgaz et al. show that the round cells secrete matrix metalloproteinases, which allow them to degrade surrounding connective tissue more effectively than elongated cells.
- Jose L. Orgaz
- , Pahini Pandya
- & Victoria Sanz-Moreno
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Naturally occurring tumours in the basal metazoan Hydra
The evolutionary origin of tumours remains largely unknown. Here, Domazet-Lošo et al. show evidence for naturally occurring tumours in the freshwater polyp, Hydra, and suggest that tumours have deep evolutionary roots.
- Tomislav Domazet-Lošo
- , Alexander Klimovich
- & Thomas C.G. Bosch
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p38 MAPK-inhibited dendritic cells induce superior antitumour immune responses and overcome regulatory T-cell-mediated immunosuppression
Dendritic cell-based approaches to induce antitumour immunity are promising, but have not shown encouraging results in clinical trials. Here the authors show that inhibition of p38 MAPK in dendritic cells increases expression of OX40L, boosting antitumour T-cell responses and dampening regulatory T-cell activity.
- Yong Lu
- , Mingjun Zhang
- & Qing Yi
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Ezh2 loss promotes development of myelodysplastic syndrome but attenuates its predisposition to leukaemic transformation
Mutations in the EZH2 gene are found in myelodysplastic syndrome (MDS) and are often accompanied by mutations in RUNX1. Here, the authors develop a mouse model of MDS and show that EZH2loss enhances the RUNX1-mediated MDS pathology.
- Goro Sashida
- , Hironori Harada
- & Atsushi Iwama
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SUMO1 modification stabilizes CDK6 protein and drives the cell cycle and glioblastoma progression
The correct timing of cyclin-dependent kinase (CDK) activity is crucial for the fidelity of the cell cycle. In this study, Bellail et al.show that CDK6 protein levels are positively regulated by SUMOylation and that this modification blocks ubiquitination and subsequent degradation.
- Anita C. Bellail
- , Jeffrey J. Olson
- & Chunhai Hao
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Disruption of astrocyte–vascular coupling and the blood–brain barrier by invading glioma cells
Astrocytic endfeet maintain endothelial tight junctions that form the blood–brain barrier (BBB), which can be damaged by invading gliomas. Here, the authors show that this damage is due to the association of gliomas with existing vessels and the displacement of astrocytic endfeet.
- Stacey Watkins
- , Stefanie Robel
- & Harald Sontheimer
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| Open Access2q36.3 is associated with prognosis for oestrogen receptor-negative breast cancer patients treated with chemotherapy
Studies have shown that breast cancer prognosis is hereditary. Here the authors show that a genetic variant in CCL20, a chemokine ligand involved in immune response, is significantly associated with breast cancer survival and may therefore represent an important therapeutic or prognostic target.
- Jingmei Li
- , Linda S. Lindström
- & Kamila Czene
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A meta-analysis of Hodgkin lymphoma reveals 19p13.3 TCF3 as a novel susceptibility locus
While Hodgkin lymphoma (HL) is a common cancer affecting young adults in Western countries, its genetic basis is poorly understood. Here, the authors carry out a genome-wide association analysis in HL patients and healthy controls; identifying a new HL risk locus and implicating TCF3in the disease aetiology.
- W. Cozen
- , M. N. Timofeeva
- & J. D. McKay
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| Open AccessRecurrent somatic mutation in DROSHA induces microRNA profile changes in Wilms tumour
Wilms tumour (WT) is the most common paediatric kidney cancer and few driver genes related to its development have been identified. Here, the authors identify DROSHAmutations that may contribute to WT tumorigenesis through their effect on primary microRNA processing.
- Giovana T. Torrezan
- , Elisa N. Ferreira
- & Dirce M. Carraro
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| Open AccessDecoding tumour phenotype by noninvasive imaging using a quantitative radiomics approach
An individual tumour is often heterogeneous and its various features can be visualised noninvasively using medical imaging. Here, the authors analyse large computed tomography data sets using radiomic algorithms to identify heterogeneity, and find that some of these tumour features have prognostic value across cancer types.
- Hugo J. W. L. Aerts
- , Emmanuel Rios Velazquez
- & Philippe Lambin
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| Open AccessMonitoring the dynamics of clonal tumour evolution in vivo using secreted luciferases
Non-invasive monitoring of solid tumour growth in mice is difficult. In this study, the authors develop a system for monitoring the secretion of luciferase either from Gaussia princeps or Cypridina noctiluca in the blood of mice harbouring luciferase-labelled tumour cells, thus providing a system to monitor two different cell populations in vivo.
- Joël P. Charles
- , Jeannette Fuchs
- & Thorsten Stiewe
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Identification of genes involved in the biology of atypical teratoid/rhabdoid tumours using Drosophila melanogaster
Atypical teratoid/rhabdoid brain tumours are characterized by loss of chromatin remodelling complex member SMARCB1. Here, using a genetic screen in Drosophila, the authors identify a number of genes involved in the detrimental effects of SMARCB1 deficiency.
- Astrid Jeibmann
- , Kristin Eikmeier
- & Martin Hasselblatt
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Engineering human tumour-associated chromosomal translocations with the RNA-guided CRISPR–Cas9 system
CRISPR and Cas9 are endonucleases that are found in bacteria and have recently been exploited for genome engineering. Here, the authors use this system in cultured mammalian cells to engineer chromosomal translocations that are found in acute myeloid leukaemia and Ewing’s sarcoma.
- R. Torres
- , M. C. Martin
- & S. Rodriguez-Perales
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Transient expression of Bcl6 is sufficient for oncogenic function and induction of mature B-cell lymphoma
Diffuse large B-cell lymphoma is an aggressive heterogeneous tumour type with poorly understood aetiology. Here, Green et al. show that transient expression of Bcl6in haematopoietic stem cells is sufficient to induce mature B-cell lymphoma, indicating that it acts as a ‘hit-and-run’ oncogene.
- Michael R. Green
- , Carolina Vicente-Dueñas
- & Isidro Sánchez-García
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| Open AccessPADI4 acts as a coactivator of Tal1 by counteracting repressive histone arginine methylation
Peptidylarginine deiminase 4 (PADI4) is a transcriptional co-regulator that converts arginine residues at histone tails to citrulline. The authors show that PADI4 interacts with the central haematopoietic transcription factor TAL1 to regulate gene expression in an erythroleukemia cell line.
- Stephan Kolodziej
- , Olga N. Kuvardina
- & Jörn Lausen
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A pan-cancer proteomic perspective on The Cancer Genome Atlas
Analyses of genome and transcriptome data are unable to accurately predict protein levels and function in tumour samples. Here, the authors carry out a comprehensive protein analysis in 3,467 samples from the cancer genome atlas, providing a resource to study the prognostic and therapeutic potential of tumour proteins.
- Rehan Akbani
- , Patrick Kwok Shing Ng
- & Gordon B. Mills
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| Open AccessClathrin light chains are required for the gyrating-clathrin recycling pathway and thereby promote cell migration
Clathrin light chain (CLC) subunits are dispensable for clathrin-mediated endocytosis of a number of cargoes. Majeed et al. report that CLCs are however required for gyrating-clathrin-dependent recycling of inactive β1-integrins, the absence of which impairs cell migration.
- Sophia R. Majeed
- , Lavanya Vasudevan
- & Frances M. Brodsky
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| Open AccessMixed lineage kinases activate MEK independently of RAF to mediate resistance to RAF inhibitors
B-Raf is mutated in many melanomas but treatment of the disease with small molecules targeting the mutant protein often results in tumour resistance. Here, the authors show that mixed lineage kinases (MLK1-4) can reactivate the B-Raf signalling pathway in the presence of inhibitors, resulting in drug resistance.
- Anna A. Marusiak
- , Zoe C. Edwards
- & John Brognard
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Nanoparticle-formulated siRNA targeting integrins inhibits hepatocellular carcinoma progression in mice
Integrin proteins regulate important cellular processes such as proliferation and differentiation. Here the authors show that siRNA-mediated knockdown of two integrin subunits slows down progression of hepatocellular carcinoma in mice by reducing activation of the METoncogene.
- Roman L. Bogorad
- , Hao Yin
- & Victor Koteliansky
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Non-invasive classification of microcalcifications with phase-contrast X-ray mammography
X-ray absorption imaging is used for early breast cancer detection but can barely identify the morphology of microcalcifications—a possible indicator of cancer. Wang et al.develop a technique to non-invasively classify different types of microcalcifications and achieve 100% sensitivity on phantom data.
- Zhentian Wang
- , Nik Hauser
- & Marco Stampanoni
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An improved monomeric infrared fluorescent protein for neuronal and tumour brain imaging
Infrared fluorescent proteins offer advantages for deep in vivo imaging thanks to the tissue-penetrating properties of infrared light. Here, Yu et al. design a monomeric infrared fluorescent protein that, when combined with expression of haeme oxygenase in cells, shows improved performance for in vivoimaging of neurons and brain tumours.
- Dan Yu
- , William Clay Gustafson
- & Xiaokun Shu
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Contribution of the R-Ras2 GTP-binding protein to primary breast tumorigenesis and late-stage metastatic disease
Ras family members have critical roles in many types of tumours but the role of R-Ras2 in cancer is unclear. Here the authors show that R-Ras2 is important in both the formation of breast primary tumours and metastasis to the lung.
- Romain M. Larive
- , Giulia Moriggi
- & Xosé R. Bustelo
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Enriched variations in TEKT4 and breast cancer resistance to paclitaxel
Paclitaxel is effective in the treatment of breast cancer but predicting which patients might respond to this drug is of clinical importance. Here, Jiang et al. show that germline mutations in TEKT4, a protein that associates with microtubules, are associated with resistance to paclitaxel therapy.
- Yi-Zhou Jiang
- , Ke-Da Yu
- & Zhi-Ming Shao
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The covalent modifier Nedd8 is critical for the activation of Smurf1 ubiquitin ligase in tumorigenesis
E3 ligases that attach ubiquitin to proteins destined for proteasomal degradation are regulated by neddylation. In this study, Xie et al. show that the HECT ligase Smurf1, which is a ubiquitin ligase, is also neddylated, and this post-translational modification enhances its ligase activity.
- Ping Xie
- , Minghua Zhang
- & Lingqiang Zhang
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Massive gene amplification drives paediatric hepatocellular carcinoma caused by bile salt export pump deficiency
Hepatocellular carcinoma (HCC) is associated with chronic inflammation, but the genetic basis of the disease remains unclear. Here, the authors report that defects in hepatocyte biliary transporters and subsequent liver inflammation induce genomic alterations that promote HCC in human and mouse.
- Fabio Iannelli
- , Agnese Collino
- & Francesca D. Ciccarelli
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S100A11 is required for efficient plasma membrane repair and survival of invasive cancer cells
The cell membrane of metastatic cells is exposed to a variety of physical and chemical stresses. Here, Jaiswal et al. show that S100A11, which is increased in expression in several cancers, is required to promote repair of cell membrane damage in invasive breast cancer cells in vitro.
- Jyoti K. Jaiswal
- , Stine P. Lauritzen
- & Jesper Nylandsted
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| Open AccessIntegrated exome and transcriptome sequencing reveals ZAK isoform usage in gastric cancer
The genetic basis of gastric cancer, the fourth most common cancer worldwide, remains poorly understood. Here, the authors sequence and analyse the exomes and transcriptomes of primary gastric tumours and cell lines, and identify a ZAK kinase isoform that may have an oncogenic role in gastric cancer.
- Jinfeng Liu
- , Mark McCleland
- & Zemin Zhang
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Protein grafting of p53TAD onto a leucine zipper scaffold generates a potent HDM dual inhibitor
The protein levels of the tumour suppressor p53 can be negatively regulated by HDM2, which is an attractive target for cancer therapy. In this study, Lee et al. graft the transactivation domain of p53 onto a scaffold protein and show that this binds to HDM2 and inhibits cancer cell growth in vitro.
- Jung-Hoon Lee
- , Eunji Kang
- & Jae Il Lee
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| Open AccessWhole-genome sequencing of bladder cancers reveals somatic CDKN1A mutations and clinicopathological associations with mutation burden
Bladder cancer is a complex genetic disease and a common cause of death due to malignancy. Here, the authors carry out whole-genome sequencing of 14 bladder cancers to characterize the genomic landscape of the disease and show that mutational burden is associated with tumour progression in these samples.
- J. -B. Cazier
- , S. R. Rao
- & F. C. Hamdy
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IKKα restoration via EZH2 suppression induces nasopharyngeal carcinoma differentiation
Nasopharyngeal carcinomas often present as undifferentiated tumours. Here, Yan et al. show that reduced expression of IKK via promoter methylation results in the undifferentiated phenotype of the tumours and that treatment with retinoic acid can reverse these features.
- Min Yan
- , Yan Zhang
- & Quentin Liu
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| Open AccessProcessed pseudogenes acquired somatically during cancer development
Germline pseudogenes have an important role in human evolution. Here, the authors analyse sequencing data from 660 cancer samples and find evidence for the formation of somatically acquired pseudogenes, a new class of mutation, which may contribute to cancer development.
- Susanna L. Cooke
- , Adam Shlien
- & Gerrit K.J. Hooijer
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The landscape of somatic mutations in epigenetic regulators across 1,000 paediatric cancer genomes
Proteins involved in epigenetic regulation are frequently mutated in several paediatric cancers. Here, Huether et al.characterize the somatic mutation frequency across 21 paediatric cancer subtypes by sequencing 633 epigenetic genes in over 1,000 tumours; generating a rich data set for investigating epigenetic dysregulation.
- Robert Huether
- , Li Dong
- & James R. Downing
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| Open AccessHarnessing photochemical internalization with dual degradable nanoparticles for combinatorial photo–chemotherapy
Photochemical internalisation is the process by which a laser source activates light sensitive compounds for cellular uptake. Here, the authors combine this technique with photo–chemo degradable polymers for the controlled uptake of chemotherapeutics into cancer cells showing increased cell death.
- George Pasparakis
- , Theodore Manouras
- & Panagiotis Argitis
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| Open AccessUltra-sensitive liquid biopsy of circulating extracellular vesicles using ExoScreen
The potential of extracellular vesicles (EVs) as cancer biomarkers is substantial. Here, Yoshioka et al. describe a sensitive technique to analyse EVs directly from blood samples of patients with colorectal cancer, highlighting a liquid biopsy technique with cancer-detection possibilities.
- Yusuke Yoshioka
- , Nobuyoshi Kosaka
- & Takahiro Ochiya
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| Open AccessPorphyrin–phospholipid liposomes permeabilized by near-infrared light
The delivery of therapeutics using an external trigger is an attractive route for the improvement of targeted disease treatment. Here, the authors have discovered a porphyrin–phospholipid liposome for light-controlled membrane permeabilization and use the system to deliver an anticancer drug in vivo.
- Kevin A. Carter
- , Shuai Shao
- & Jonathan F. Lovell
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| Open AccessA DERL3-associated defect in the degradation of SLC2A1 mediates the Warburg effect
Defective proteins or functional proteins that are no longer needed can be degraded in the endoplasmic reticulum. In this study, Lopez-Serra et al.show that DERL3, which is involved in protein degradation in the endoplasmic reticulum, is aberrantly silenced in cancer, leading to activation of a glucose transporter and dysregulated glycolysis.
- Paula Lopez-Serra
- , Miguel Marcilla
- & Manel Esteller
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Three-layered polyplex micelle as a multifunctional nanocarrier platform for light-induced systemic gene transfer
Light-controlled mechanisms for the delivery of drug molecules to cells is a promising route for non-invasive disease therapy. Here, the authors develop a photosensitive polymeric micelle for light-induced gene transfection and show its effectiveness in vivovia systemic administration.
- Takahiro Nomoto
- , Shigeto Fukushima
- & Kazunori Kataoka
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Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids
Pulmonary carcinoids account for about 2% of pulmonary neoplasms. Here, the authors carry out gene copy number analysis, genome/exome, and transcriptome sequencing of pulmonary carcinoids and identify frequent mutations in chromatin-remodelling genes that can drive tumorigenesis in these tumours.
- Lynnette Fernandez-Cuesta
- , Martin Peifer
- & Roman K. Thomas
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Lymph node-independent liver metastasis in a model of metastatic colorectal cancer
It remains unclear whether colorectal cancer metastases in the liver arise from intermediate metastases in the lymph nodes or directly from the primary tumour. Enquist et al.demonstrate lymph node-independent metastasis using a mouse model in which tumours are transplanted directly onto the luminal surface of the colon.
- Ida B. Enquist
- , Zinaida Good
- & Kevin G. Leong
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Spontaneous tumour regression in keratoacanthomas is driven by Wnt/retinoic acid signalling cross-talk
Keratoacanthomas are skin tumours that spontaneously regress but the mechanisms leading to regression are unknown. Here, using a mouse chemical carcinogenesis model, the authors show that tumour regression is driven by activation of retinoic acid signalling that induces Wnt inhibition and tumour differentiation.
- Giovanni Zito
- , Ichiko Saotome
- & Valentina Greco
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