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| Open AccessMonocytic and granulocytic myeloid derived suppressor cells differentially regulate spatiotemporal tumour plasticity during metastatic cascade
Myeloid-derived suppressive cells (MDSCs) promote metastasis. Here, the authors show that the monocytic MDSCs subset promotes epithelial to mesenchymal transition at the primary site while the granulocytic subset promotes the reverse transition at the metastatic site enabling dynamic tumour cells plasticity.
- Maria Ouzounova
- , Eunmi Lee
- & Hasan Korkaya
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Article
| Open AccessPhosphorylation of Rab-coupling protein by LMTK3 controls Rab14-dependent EphA2 trafficking to promote cell:cell repulsion
Ephrin receptors mediate contact inhibition, but their intracellular trafficking during this process is unknown. Here the authors show that EphA2 receptor trafficking is regulated by the Rab GTPase effector Rab-coupling protein, which associates with Rab14-endosomes upon LMTK3-mediated phosphorylation.
- Christine Gundry
- , Sergi Marco
- & Jim C. Norman
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Article
| Open AccessLoss of ERα induces amoeboid-like migration of breast cancer cells by downregulating vinculin
Estrogen receptor alpha (ERα)-negative cells, which are enriched during endocrine therapy, are associated with metastatic relapse of breast cancer. Here the authors show that ERα inhibits breast cancer metastasis and suggest that ERα suppresses the amoeboid-like migration of breast cancer cells by upregulating vinculin.
- Yuan Gao
- , Zhaowei Wang
- & Yingqi Zhang
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Article
| Open AccessMalignant extracellular vesicles carrying MMP1 mRNA facilitate peritoneal dissemination in ovarian cancer
Ovarian cancer is particularly deadly because it is difficult to detect at the pre-metastatic stage; extracellular vesicles (EVs) on the other hand are involved in the pre-metastatic niche preparation. Here the authors show that EVs mediate ovarian cancer metastasis in the peritoneal area by targeting the mesothelium.
- Akira Yokoi
- , Yusuke Yoshioka
- & Takahiro Ochiya
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Article
| Open AccessCancer cell-secreted IGF2 instigates fibroblasts and bone marrow-derived vascular progenitor cells to promote cancer progression
Cancer cells can affect cancer progression by producing systemic effects. Here, the authors show that IGF2 produced by oesophageal cancer cells increases secretion of VEGF from cancer-associated fibroblasts resulting in systemic mobilization of bone marrow-derived cells and increased metastases.
- Wen Wen Xu
- , Bin Li
- & Annie L. M. Cheung
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Article
| Open AccessExpression of β-globin by cancer cells promotes cell survival during blood-borne dissemination
Circulating tumour cells contribute to metastatic spread. Here the authors find that beta-chain of haemoglobin is overexpressed in those cells and protects them from oxidative stress, prolonging their survival in circulation and thereby increasing the likelihood of metastasis formation.
- Yu Zheng
- , David T. Miyamoto
- & Daniel A. Haber
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Article
| Open AccessMicroenvironment-derived factors driving metastatic plasticity in melanoma
Phenotype switching is a form of plasticity that allows melanoma cancer cells that leave the primary tumour to invade secondary sites, to switch from an invasive to a proliferative state. Here the authors identify EDN3, and its synthetic enzyme ECE2, as a regulator of melanoma plasticity in the microenvironment.
- Isabella S. Kim
- , Silja Heilmann
- & Richard M. White
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Article
| Open AccessSnail reprograms glucose metabolism by repressing phosphofructokinase PFKP allowing cancer cell survival under metabolic stress
Cancer cell survival under metabolic stress is a critical step for metastasis. Here, the authors show that under glucose deprivation, Snail, a key regulator of the metastatic process, promotes survival by diverting glucose to the pentose phosphate pathway through repression of phosphofructokinase PFKP.
- Nam Hee Kim
- , Yong Hoon Cha
- & Hyun Sil Kim
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Article
| Open AccessHOPX hypermethylation promotes metastasis via activating SNAIL transcription in nasopharyngeal carcinoma
HOPX is a transcription factor epigenetically silenced in several cancers. Here the authors, by analysing methylation profiles, identify HOPX as a suppressor of metastasis in nasopharyngeal carcinoma: mechanistically HOPX inhibitsSNAILtranscription through deacetylation-mediated silencing.
- Xianyue Ren
- , Xiaojing Yang
- & Jun Ma
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Article
| Open AccessTumour-derived Interleukin 35 promotes pancreatic ductal adenocarcinoma cell extravasation and metastasis by inducing ICAM1 expression
Interleukin-35 (IL-35) is an immune suppressive cytokine produced by T-cells. Here, the authors show that IL-35 is overexpressed by human pancreatic cancer cells and show, in a mouse model, that IL-35 promotes metastasis in an autocrine/paracrine manner via induction of ICAM-1 expression.
- Chongbiao Huang
- , Na Li
- & Jihui Hao
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Article
| Open AccessFluid shear stress activates YAP1 to promote cancer cell motility
Fluid frictional forces around cancer cells influence chemokine production and delivery of chemotherapeutic drugs but it is unclear if they directly impact tumour biology through biomechanical effects. Here, the authors show that wall shear stress stimulates cancer cell migration through a ROCK–LIMK–YAP axis.
- Hyun Jung Lee
- , Miguel F. Diaz
- & Pamela L. Wenzel
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Article
| Open AccessMicroRNA-182 targets SMAD7 to potentiate TGFβ-induced epithelial-mesenchymal transition and metastasis of cancer cells
SMAD7 is a transcriptional target and a negative regulator of TGFβ signalling forming a negative feedback loop. Here the authors show that in cancer cells TGFβ activates the expression of microRNA-182 that suppresses SMAD7 protein, promoting TGFβ-mediated breast tumour invasion and bone metastasis.
- Jingyi Yu
- , Rong Lei
- & Guohong Hu
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Article
| Open AccessA neuronal network of mitochondrial dynamics regulates metastasis
Mitochondria have a controversial role in cancer. Here, the authors demonstrate the reprogramming of a neuronal network of mitochondrial trafficking in tumor cells, and identify Syntaphilin as a key protein that suppresses organelle dynamics thereby blocking chemotaxis and metastasis in mice.
- M. Cecilia Caino
- , Jae Ho Seo
- & Dario C. Altieri
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Article
| Open AccessGALNT14 promotes lung-specific breast cancer metastasis by modulating self-renewal and interaction with the lung microenvironment
Polypeptide N-acetyl-galactosaminyltransferases (GALNTs) are associated with cancer, but their function in organ-specific metastasis is unclear. Here the authors show that GALNT14 promotes breast cancer metastasis to the lung by enhancing the initiation of metastatic colonies and subsequent growth.
- Ki-Hoon Song
- , Mi So Park
- & Mi-Young Kim
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Article
| Open AccessSCN4B acts as a metastasis-suppressor gene preventing hyperactivation of cell migration in breast cancer
The capacity of cancer cells to migrate is intimately linked to their ability to induce metastasis. Here the authors show that the sodium channel β4 subunit regulates breast cancer cell migration via inhibition of RhoA activation, independently from its function as an auxiliary protein of the sodium channel.
- Emeline Bon
- , Virginie Driffort
- & Sébastien Roger
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Article
| Open AccessCELF1 is a central node in post-transcriptional regulatory programmes underlying EMT
Epithelial-to-mesenchymal transition is a key process in tumorigenesis but little is known about the molecular mechanism regulating such process at the translational level. Here, the authors identify a subset of mRNAs important for this process that are specifically modulated by the RNA-binding protein CELF1.
- Arindam Chaudhury
- , Shebna Cheema
- & Joel R. Neilson
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Article
| Open AccessHistone variant H3F3A promotes lung cancer cell migration through intronic regulation
Histone variants act as transcriptional activators and repressors and have been linked to cancer progression. Park and Choi et al. show that the histone H3.3 overexpression is associated with early-stage lung cancer, and promotes cancer cell migration by upregulating a G-protein-coupled receptor.
- Seong-Min Park
- , Eun-Young Choi
- & In-Hoo Kim
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Article
| Open AccessMetastatic progression is associated with dynamic changes in the local microenvironment
Metastatic colonization—the growth of single metastatic cells or small lesions into gross metastases—is poorly understood. Here, the authors characterize the natural history of metastatic growth and assess the impact of chemotherapy in an autochthonous model of pancreatic cancer.
- Nicole M. Aiello
- , David L. Bajor
- & Ben Z. Stanger
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Article
| Open AccessDiscontinuation of anti-VEGF cancer therapy promotes metastasis through a liver revascularization mechanism
Anti-VEGF therapy often produces limited beneficial effects in cancer patients. Here, the authors show that discontinuation of anti-VEGF cancer therapy in xenografts-bearing mice increases cancer cells extravasation and intravasation in liver through the host-derived VEGF.
- Yunlong Yang
- , Yin Zhang
- & Yihai Cao
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Article
| Open AccessDecreased NK-cell tumour immunosurveillance consequent to JAK inhibition enhances metastasis in breast cancer models
JAK inhibitors are currently undergoing evaluation in clinical trials for advanced breast cancer. Here, the authors show that JAK pathway inhibition increases metastasis in mouse models of breast cancer by impairing NK anti-tumour activity and that these side effects can be overcome by addition of IL-15.
- Alessia Bottos
- , Dagmar Gotthardt
- & Nancy E. Hynes
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Article
| Open AccessBeta 1-integrin–c-Met cooperation reveals an inside-in survival signalling on autophagy-related endomembranes
Cooperative signalling between receptor tyrosine kinases (RTKs) and integrins is thought to occur at the cell surface. Here the authors show that β1 integrin influences signalling of an RTK, c-Met, from a novel intracellular compartment they call autophagy-related endomembranes.
- Rachel Barrow-McGee
- , Naoki Kishi
- & Stéphanie Kermorgant
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Article
| Open AccessWhole-genome plasma sequencing reveals focal amplifications as a driving force in metastatic prostate cancer
The genomic features of metastatic prostate cancer are beginning to be understood. Here, the authors performed whole genome sequencing of plasma samples from these patients and found a high plasticity of the cancer genomes with newly occurring focal amplifications as a driving force in progression.
- Peter Ulz
- , Jelena Belic
- & Michael R. Speicher
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Article
| Open AccessSuspension survival mediated by PP2A-STAT3-Col XVII determines tumour initiation and metastasis in cancer stem cells
Tumour initiating cells (TICs) are anoikis resistant in suspension culture and they are critical for initiating tumorigenesis in vivo. Here, the authors show that these features are promoted by hemidesmosome-like structures enriched in laminin V and collagen XVII 5 upregulated in TICs by phospho-STAT3 whose levels are increased through PP2A inactivation.
- Chen-Chi Liu
- , Shih-Pei Lin
- & Shih-Chieh Hung
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Article
| Open AccessCytoplasmic cyclin D1 regulates cell invasion and metastasis through the phosphorylation of paxillin
Previous studies suggest that Cyclin D1 may regulate cell adhesion and migration but the mechanisms underlying such regulation and the relevance to cancer development are unknown. Here, Fusté et al. show that Cyclin D1/Cdk4 phosphorylates paxillin and thereby promotes cellular migration and metastasis.
- Noel P. Fusté
- , Rita Fernández-Hernández
- & Eloi Garí
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Article
| Open AccessThe PDGF-BB-SOX7 axis-modulated IL-33 in pericytes and stromal cells promotes metastasis through tumour-associated macrophages
Elevated IL-33 levels have been correlated with metastasis and poor prognosis. Here the authors show in mouse tumour xenograft models that PDGF-BB produced by tumour cells induces IL-33 via Sox7 in tumour pericytes, and IL-33 promotes metastasis through its effects on tumour-associated macrophages.
- Yunlong Yang
- , Patrik Andersson
- & Yihai Cao
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Article
| Open AccessHighly variable cancer subpopulations that exhibit enhanced transcriptome variability and metastatic fitness
Phenotypic and genetic intra-tumor heterogeneity have an important role in cancer progression and therapeutic resistance. Here, the authors show that phenotypically variable tumor subpopulations exhibit higher metastatic potential and display enhanced intra-clonal transcriptomic variability, likely promoted by deregulated spliceosome activity.
- Alexander Nguyen
- , Mitsukuni Yoshida
- & Sohail F. Tavazoie
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Article
| Open AccessDysregulation of miRNAs-COUP-TFII-FOXM1-CENPF axis contributes to the metastasis of prostate cancer
The orphan nuclear receptor COUP-TFII is highly expressed in metastatic prostate cancers and its overexpression accelerates prostate tumour progression in mouse models. Here, the author show that that loss of miR-101 and miR-27a in prostate cancer cells can lead to COUP-TFII expression which in turn directly regulates FOXM1 and CENPFfavouring prostate cancer metastasis.
- Shih-Chieh Lin
- , Chung-Yang Kao
- & Ming-Jer Tsai
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Article
| Open AccessInduction of IL-25 secretion from tumour-associated fibroblasts suppresses mammary tumour metastasis
Interleukin-25 has been reported to have anticancer activity with very little effect on non-malignant cells. Here, the authors show that a synthetic phytochemical can be used to induce the secretion of Interleukin-25 from tumour associated fibroblasts resulting in impaired tumour metastasis.
- Shu-Yi Yin
- , Feng-Yin Jian
- & Ning-Sun Yang
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Article
| Open AccessRAS signalling through PI3-Kinase controls cell migration via modulation of Reelin expression
Ras signalling through PI3K kinase has an important role in tumour initiation and progression. Here, the authors show that the interaction of Ras with PI3-Kinase p110α and the subsequent activation of Rac-GTPase impairs cell -cell interaction by blocking the downstream Reelin/E-cadherin, thus resulting in cell migration.
- Esther Castellano
- , Miriam Molina-Arcas
- & Julian Downward
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Article
| Open AccessELL targets c-Myc for proteasomal degradation and suppresses tumour growth
The expression of the oncogene Myc is carefully controlled and dysregulation often leads to cancer. Here, the authors describe an E3 ligase for Myc—ELL—and show that it likely controls the ubiquitination and degradation of Myc.
- Yu Chen
- , Chi Zhou
- & Wuhan Xiao
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Article
| Open AccessVEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread
Signals through VEGF receptor 2 (VEGFR2) increase vascular permeability, promoting cancer progression. Here the authors show that a point mutation in VEGFR2 preventing its auto-phosphorylation leads to reduced metastatic spread and improved response to chemotherapy in tumor-bearing mice, without affecting tumor inflammation.
- Xiujuan Li
- , Narendra Padhan
- & Lena Claesson-Welsh
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Article
| Open AccessDifferential TGFβ pathway targeting by miR-122 in humans and mice affects liver cancer metastasis
MiR-122 levels correlate with metastasis in human liver cancer but not in mouse models. Here the authors show that miR-122 targets TGFßR1 in mice but TGFß1 in humans, that swapping this specificity affects metastasis, and that many other receptor-ligand pairs are differentially targeted by miRNAs across species.
- Shenyi Yin
- , Yu Fan
- & Jianzhong Jeff Xi
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Article
| Open AccessTOM1L1 drives membrane delivery of MT1-MMP to promote ERBB2-induced breast cancer cell invasion
ERBB2 overexpression in human breast cancer leads to invasion and metastasis. Here the authors report that ERBB2 induces indirect phosphorylation of TOM1L1 that promotes trafficking of the metalloprotease MT1-MMP to invadopodia, which leads to tumour cell invasion.
- Clément Chevalier
- , Guillaume Collin
- & Christine Benistant
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Article
| Open AccessThe histone variant H2A.X is a regulator of the epithelial–mesenchymal transition
The histone H2A variants are involved in DNA repair, gene regulation and cancer development. In this study, the authors unravel an additional role for H2A.X in the regulation of mesenchymal-like traits and activation of the EMT transcription factors, Slug and ZEB1, in colon cancer cells.
- Urbain Weyemi
- , Christophe E. Redon
- & William M. Bonner
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Article
| Open AccessThe mRNA-edited form of GABRA3 suppresses GABRA3-mediated Akt activation and breast cancer metastasis
GABRA3, a subunit of the GABA receptor, is often highly expressed in brain metastasis and breast cancers. Here, the authors demonstrated that GABRA3 activates AKT to promote breast cancer cell invasion and that the A-to-I edited form of GABRA3, specifically expressed in noninvasive breast cancers, can suppress the function of wild type GABRA3.
- Kiranmai Gumireddy
- , Anping Li
- & Qihong Huang
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Article
| Open AccessA monoclonal antibody against KCNK9 K+ channel extracellular domain inhibits tumour growth and metastasis
The potassium channel KCNK9 mediates important biological processes and is often overexpressed in breast and lung cancers. In this study, the authors developed a specific monoclonal antibody against the extracellular domain of KCNK9 and show that it inhibits cancer growth and metastasis in vivothrough both cell autonomous and immune-dependent cellular cytotoxicity.
- Han Sun
- , Liqun Luo
- & Min Li
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Article
| Open AccessC1q acts in the tumour microenvironment as a cancer-promoting factor independently of complement activation
C1q is known to initiate the activation of the complement classical pathway. Here, the authors show the C1q is expressed in the tumour microenvironment and can promote cancer cell migration and adhesion in a complement activation-independent manner.
- Roberta Bulla
- , Claudio Tripodo
- & Francesco Tedesco
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Article
| Open AccessBcl-xL promotes metastasis independent of its anti-apoptotic activity
Bcl-xL is an anti-apoptotic protein that has also been implicated in metastasis. In this study, the authors show that nuclear Bcl-xL promotes metastasis by regulating TGFβ signaling, which is independent of the anti-apoptotic activity of Bcl-xL.
- Soyoung Choi
- , Zhengming Chen
- & Yi-Chieh Nancy Du
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Article
| Open AccessPhysical nanoscale conduit-mediated communication between tumour cells and the endothelium modulates endothelial phenotype
Cancer cells and stromal cells have been shown to pass cellular information between each other via exosomes. Here, the authors demonstrate that cancer cells can communicate with endothelial cells through nanoscale membrane bridges, and demonstrate that microRNAs are passed through these nanobridges, which modulates endothelial cell phenotype.
- Yamicia Connor
- , Sarah Tekleab
- & Shiladitya Sengupta
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Article
| Open AccessFrequent alterations in cytoskeleton remodelling genes in primary and metastatic lung adenocarcinomas
Despite lung adenocarcinoma having a high global mortality, the genetic mutations present in Asian patients are uncharacterized. Here the authors use genomic and transcriptomic analysis to identify thirteen significantly affected genes, including RHPN2, GLI3, MRC2, TP53 and IQGAP3.
- Kui Wu
- , Xin Zhang
- & Jianxing He
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Article
| Open AccessIRAK1 is a therapeutic target that drives breast cancer metastasis and resistance to paclitaxel
Triple negative breast cancer (TNBC) patients often acquire resistant to chemotherapy. In this study, the authors identify the IRAK1 as the crucial driver of NF-κB-related cytokine secretion involved in TNBC metastasis and therapy resistance.
- Zhen Ning Wee
- , Siti Maryam J. M. Yatim
- & Qiang Yu
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Article
| Open AccessA splicing variant of Merlin promotes metastasis in hepatocellular carcinoma
Merlin plays a crucial role as a tumour suppressor in liver tumorigenesis. Here, the authors show that a splicing variant of Merlin that lacks exons 2,3 and 4 (Δ2–4Merlin) is highly expressed in hepatocarcinoma and promotes tumour metastasis by interfering with the binding of wild-type Merlin to ß-catenin.
- Zai-Li Luo
- , Shu-Qun Cheng
- & Zhong Li
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Article
| Open AccessBAP1 promotes breast cancer cell proliferation and metastasis by deubiquitinating KLF5
The zinc finger-containing transcription factor KLF5 drives cell proliferation and migration. Here, the authors show that the debuquitinase BAP1 directly stabilizes KLF5, thus promoting basal-like breast cancer cell-cycle progression and metastasis.
- Junying Qin
- , Zhongmei Zhou
- & Ceshi Chen
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Epigenetic regulation of Smad2 and Smad3 by profilin-2 promotes lung cancer growth and metastasis
Smad signalling has been implicated in tumour and metastases formation. Here, Tang et al.show that profilin-2 enhances Smad signalling and tumour growth via an epigenetic mechanism, and that Smad expression correlates with an unfavourable prognosis of lung cancer patients.
- Yun-Neng Tang
- , Wei-Qiao Ding
- & Jian-Guo Song
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In vivo capture and label-free detection of early metastatic cells
Tumour metastasis is a significant source of mortality, often because it is detected at an advanced stage. In this study, in an effort to identify metastasis at an early stage, Azarin et. al. capture and image metastasizing cells in mice in vivousing a biomaterial scaffold.
- Samira M. Azarin
- , Ji Yi
- & Lonnie D Shea
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Article
| Open AccessMRI detection of breast cancer micrometastases with a fibronectin-targeting contrast agent
Increased fibronectin expression is associated with high-risk breast cancer and metastasis. Here, the authors develop a penta-peptide CREKA-targeted MRI contrast agent that binds to fibronectin and show its potential for early detection of breast cancer and micrometastasis.
- Zhuxian Zhou
- , Mohammed Qutaish
- & Zheng-Rong Lu
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Article
| Open AccessSTAT3 regulated ARF expression suppresses prostate cancer metastasis
IL6-STAT3 signaling is activated in prostate cancer, however inhibiting this pathway has not lead to a survival advantage in patients. Here, Pencik et al.show that loss of the IL6-STAT3 axis in mice and humans leads to metastasis due to loss of ARF, unravelling STAT3 and ARF as potential prognostic markers in prostate cancer.
- Jan Pencik
- , Michaela Schlederer
- & Lukas Kenner
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Article
| Open AccessEpstein–Barr virus-encoded microRNA BART1 induces tumour metastasis by regulating PTEN-dependent pathways in nasopharyngeal carcinoma
Epstein–Barr virus is associated with nasopharyngeal carcinoma and previous studies have focused on the role of viral proteins in tumour pathology. Here, the authors show that a viral miRNA targets the host protein PTEN and has a critical role in the late stage of nasopharyngeal carcinoma by driving tumour metastasis.
- Longmei Cai
- , Yanfen Ye
- & Xin Li
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Article |
Targeted inhibition of fascin function blocks tumour invasion and metastatic colonization
As metastasis requires cellular machinery of migration and invasion, interfering with these functions is a promising anticancer strategy. Here the authors show that a structurally novel fascin inhibitor blocks filopodia formation, migration and invasion, and effectively inhibits metastasis in mice.
- Fang-Ke Huang
- , Shaoqin Han
- & Xin-Yun Huang