Featured
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| Open AccessPAK4 suppresses RELB to prevent senescence-like growth arrest in breast cancer
Oncogene induced senescence protects cells from unrestricted growth and cancer. Here, the authors show that PAK4 overrides this senescence in breast cancer cells through phosphorylation of RELB, thereby inhibiting transcription of the senescence regulator C/EBPβ.
- Tânia D. F. Costa
- , Ting Zhuang
- & Staffan Strömblad
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Article
| Open AccessInsight into genetic predisposition to chronic lymphocytic leukemia from integrative epigenomics
The definition of regulatory landscape at chronic lymphocytic leukaemia (CLL) risk loci is limited. Here, the authors perform an epigenomic characterisation of 42 known risk loci in CLL and normal B cells at different developmental stages and show active chromatin and target genes in the risk loci.
- Helen E. Speedy
- , Renée Beekman
- & José I. Martín-Subero
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Article
| Open AccessA STAT3-based gene signature stratifies glioma patients for targeted therapy
STAT3 activates distinct transcriptional programmes within cancer cells. In this study, the authors find that, in glioma, a STAT3-mediated expression signature can stratify patients for targeted precision therapy.
- Melanie Si Yan Tan
- , Edwin Sandanaraj
- & Carol Tang
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Article
| Open AccessMYC competes with MiT/TFE in regulating lysosomal biogenesis and autophagy through an epigenetic rheostat
Genes related to lysosomal and autophagic systems are transcriptionally regulated by the Mit/TFE family of transcription factors. Here the authors show that MYC, in association with HDACs, suppresses the expression of lysosomal and autophagy genes by competing with the Mit/TFE transcription factors for occupancy of their target gene promoters.
- Ida Annunziata
- , Diantha van de Vlekkert
- & Alessandra d’Azzo
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Article
| Open AccessProteogenomic landscape of squamous cell lung cancer
Squamous cell lung cancer has dismal prognosis due to the dearth of effective treatments. Here, the authors perform an integrated proteogenomic analysis of the disease, revealing three proteomics-based subtypes and suggesting potential therapeutic opportunities.
- Paul A. Stewart
- , Eric A. Welsh
- & Eric B. Haura
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Article
| Open AccessComprehensive transcriptomic analysis of cell lines as models of primary tumors across 22 tumor types
Cell lines are used ubiquitously in cancer research but how well they represent the tumor type they were derived from is variable. Here, the authors compare transcriptomic profiles of 22 tumor types and cell lines and propose a new comprehensive cell line panel for pan-cancer studies.
- K. Yu
- , B. Chen
- & M. Sirota
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Article
| Open AccessARID1A and PI3-kinase pathway mutations in the endometrium drive epithelial transdifferentiation and collective invasion
PIK3CA mutations and ARID1A loss co-exist in endometrial neoplasms. Here, the authors show that these co-mutations drive gene expression profiles correlated with differential chromatin accessibility and ARID1A binding in the endometrial epithelium, resulting in partial EMT and myometrial invasion.
- Mike R. Wilson
- , Jake J. Reske
- & Ronald L. Chandler
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Article
| Open AccessSupramolecular trap for catching polyamines in cells as an anti-tumor strategy
Polyamines are essential for cell growth and are frequently increased in concentration in cancer cells. Here, the authors use a macrocycle to generate a supramolecular trap, which depletes the polyamines in cells, induces apoptosis and reduces cancer cell growth in mice.
- Junyi Chen
- , Hanzhi Ni
- & Chunju Li
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Article
| Open AccessCamouflaging bacteria by wrapping with cell membranes
The use of engineered bacteria for biomedical applications is limited by side effects such as inflammatory response. Here the authors engineer cell membrane coated bacteria as in vivo tumor imaging agents, and show that these generate a lower inflammatory response and reduced macrophage clearance.
- Zhenping Cao
- , Shanshan Cheng
- & Jinyao Liu
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Article
| Open AccessMYC paralog-dependent apoptotic priming orchestrates a spectrum of vulnerabilities in small cell lung cancer
The expression of oncogenic MYC paralogs in small cell lung cancer is mutually exclusive. In this study, the authors show that MYC, but not MYCN or MYCL, represses BCL2, resulting in cells that are uniquely sensitive to apoptosis, and find that CHK1 and AURKA inhibitors may be useful for treating these cancers.
- Marcel A. Dammert
- , Johannes Brägelmann
- & Martin L. Sos
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Article
| Open AccessLncRNA GLCC1 promotes colorectal carcinogenesis and glucose metabolism by stabilizing c-Myc
lncRNA and cellular metabolism are frequently dysregulated in cancer. In this study, the authors discover the lncGLCC1 is increased in colorectal cancer cells under glucose starvation conditions and correlates with poor prognosis in this cancer.
- Jiayin Tang
- , Tingting Yan
- & Jing-Yuan Fang
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Article
| Open AccessSelective inactivation of hypomethylating agents by SAMHD1 provides a rationale for therapeutic stratification in AML
In acute myeloid leukemia, hypomethylating agents decitabine and azacytidine are used interchangeably. Here, the authors show that the major metabolite of decitabine, but not azacytidine, is subject to SAMHD1 inactivation, highlighting SAMHD1 as a potential biomarker and therapeutic target
- Thomas Oellerich
- , Constanze Schneider
- & Jindrich Cinatl Jr.
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Article
| Open AccessA one-gate elevator mechanism for the human neutral amino acid transporter ASCT2
How the human Alanine Serine Cysteine Transporter 2 (ASCT2) binds its substrates, neutral amino acids, and releases them on the cytoplasmic side remains unclear. Here authors present an inward-open structure of the human ASCT2 which shows that a hairpin serves as a gate in the inward-facing state.
- Alisa A. Garaeva
- , Albert Guskov
- & Cristina Paulino
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Article
| Open AccessDetailed modeling of positive selection improves detection of cancer driver genes
Finding driver genes sheds lights on the biological mechanisms propelling the development of a tumour, and can suggest therapeutic strategies. Here, the authors develop driverMAPS, a model-based approach to identify driver genes, and apply it to TCGA datasets.
- Siming Zhao
- , Jun Liu
- & Xin He
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Article
| Open AccessER-residential Nogo-B accelerates NAFLD-associated HCC mediated by metabolic reprogramming of oxLDL lipophagy
Non alcoholic fatty liver disease (NAFLD) associates with an elevated risk of developing hepatocellular carcinoma (HCC). Here, the authors find that Nogo-B, an endoplasmic reticulum resident protein, is upregulated by lipid uptake and acts as an oncogene in NAFLD-associated HCC by promoting lipid droplet breakdown by lipophagy and triggering Hippo pathway dysregulation
- Yuan Tian
- , Bin Yang
- & Pengyuan Yang
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Article
| Open AccessTargeting photodynamic and photothermal therapy to the endoplasmic reticulum enhances immunogenic cancer cell death
Reactive oxygen species induced by endoplasmic reitculum stress can be exploited for cancer therapy. Here, nanoparticles are targetted to the endoplasmic reticulum and, when accompanied by PDT, produce stress resulting in calreticulin exposure on the cell surface, which activates dendritic cells.
- Wei Li
- , Jie Yang
- & Jian You
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Article
| Open AccessRegulation of antitumour CD8 T-cell immunity and checkpoint blockade immunotherapy by Neuropilin-1
Neuropilin-1 (Nrp-1) is a marker for CD4 + regulatory T cells. Here the authors show that Nrp-1 is co-expressed with PD-1 on a subset of CD8 tumour-infiltrating T lymphocytes and inhibits T-cell migration and cytotoxicity when bound by its ligand semaphorin-3A, while blockade of Nrp-1 synergises with anti-PD-1 to promote antitumour immunity in mouse tumour models.
- Marine Leclerc
- , Elodie Voilin
- & Fathia Mami-Chouaib
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Article
| Open AccessJMJD6 is a tumorigenic factor and therapeutic target in neuroblastoma
Although the gain in chromosome 17q21-ter is commonly associated with neuroblastoma, it is not clear which gene of this region mediates tumorigenesis. Here, the authors are showing that JMJD6, which locates in that region, is a neuroblastoma tumorigenic factor.
- Matthew Wong
- , Yuting Sun
- & Tao Liu
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Article
| Open AccessBioinspired lipoproteins-mediated photothermia remodels tumor stroma to improve cancer cell accessibility of second nanoparticles
The stromal cells and extracellular matrix hamper nanoparticle access to cancer cells and their anti-cancer efficacy. Here, the authors report a bioinspired lipoprotein (bLP) for photothermal remodelling of tumour stroma and show this to improve subsequent bLP accessibility to cancer cells.
- Tao Tan
- , Haiyan Hu
- & Yaping Li
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Article
| Open AccessERAP1 promotes Hedgehog-dependent tumorigenesis by controlling USP47-mediated degradation of βTrCP
ERAP1 is an endoplasmic reticulum aminopeptidase that trims MHC Class-I peptides for antigen presentation. Here, the authors show that ERAP1 enhances Hedgehog signalling by sequestering USP47 from βTrCP and promoting tumorigenesis through βTrCP degradation and increased Gli protein stability.
- Francesca Bufalieri
- , Paola Infante
- & Lucia Di Marcotullio
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Article
| Open AccessRIF1 promotes replication fork protection and efficient restart to maintain genome stability
Replication fork degradation can result in genome instability. Here authors reveal a role for Rif1 protein in protecting stalled replication forks from undergoing extensive, DNA2-dependent, degradation.
- Chirantani Mukherjee
- , Vivek Tripathi
- & Arnab Ray Chaudhuri
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Article
| Open AccessMethylation analysis of plasma DNA informs etiologies of Epstein-Barr virus-associated diseases
Epstein-Barr virus (EBV) is associated with different malignant diseases and circulating EBV DNA is a biomarker for nasopharyngeal carcinoma (NPC). Here, the authors report that plasma EBV DNA methylation profiles show disease-associated patterns and can help to distinguish NPC and non-NPC subjects.
- W. K. Jacky Lam
- , Peiyong Jiang
- & Y. M. Dennis Lo
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Article
| Open AccessIntegrated analyses of murine breast cancer models reveal critical parallels with human disease
Mouse models are an essential tool in breast cancer research. Here, the authors present the genomic and transcriptomic profiles of two widely used mouse models, revealing parallels with the human disease specifically with metastasis and treatment response.
- Jonathan P. Rennhack
- , Briana To
- & Eran R. Andrechek
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Article
| Open AccessA ZEB1/p53 signaling axis in stromal fibroblasts promotes mammary epithelial tumours
In epithelial cells Zeb1 is involved in the epithelial to mesenchymal transition. In this study, the authors show in a mouse model of breast cancer, that Zeb1 expression in stromal cells is required for tumour formation and metastasis.
- Rong Fu
- , Chen-Feng Han
- & Zhao-Qiu Wu
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Article
| Open AccessSubtype-specific secretomic characterization of pulmonary neuroendocrine tumor cells
Secreted proteins present a rich resource of potential cancer biomarkers. Here, the authors use mass spectrometry to analyze secretome remodeling in pulmonary neuroendocrine lung cancer cell lines and validate potential biomarkers and therapeutic targets in vitro and in mouse models.
- Xu-Dong Wang
- , Rongkuan Hu
- & Yonghao Yu
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Article
| Open Accessβ-arrestin1/YAP/mutant p53 complexes orchestrate the endothelin A receptor signaling in high-grade serous ovarian cancer
YAP and mutant p53 crosstalk to regulate transcriptional processes in cancers. Here, the authors show that endothelin-1 mediated activation of β-arrestin interacts with YAP to recruit mutant p53 to the TEAD/YAP complex to promote metastasis and chemoresistance in ovarian cancer.
- Piera Tocci
- , Roberta Cianfrocca
- & Anna Bagnato
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Article
| Open AccesscircTP63 functions as a ceRNA to promote lung squamous cell carcinoma progression by upregulating FOXM1
Circular RNAs are known to regulate cancer. Here, the authors show that the circular RNA circTP63 promotes lung squamous cell carcinoma by competing with endogenous RNA to upregulate FOXM1.
- Zhuoan Cheng
- , Chengtao Yu
- & Wenxin Qin
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Article
| Open AccessProbing the impact of sulfur/selenium/carbon linkages on prodrug nanoassemblies for cancer therapy
Prodrug-based self-assembled nanoparticles have emerged as an efficient drug delivery system (DDS) for cancer therapy. Here, the authors show that the type of bond in prodrug assemblies influences the efficiency of the DDS on several different levels.
- Bingjun Sun
- , Cong Luo
- & Jin Sun
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Article
| Open AccessMolecular retargeting of antibodies converts immune defense against oncolytic viruses into cancer immunotherapy
The efficacy of oncolytic adenoviruses is limited by strong immune responses being induced against the oncolytic virus itself. Here, the authors generate a bispecific molecule capable of redirecting the adenovirus-specific antibodies to tumour cells and show this induces immune mediated cancer growth inhibition and enhances the therapeutic efficacy of viral oncolysis.
- Julia Niemann
- , Norman Woller
- & Florian Kühnel
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Article
| Open AccessCytomembrane nanovaccines show therapeutic effects by mimicking tumor cells and antigen presenting cells
Cancer vaccines often fail to generate clinically relevant effects. Here, the authors generate a nanosized cytomembrane vaccine based on fusion between dendritic cells and cancer cells, and show them to activate anti-tumor immune responses via their antigen presenting and T-cell activating functions.
- Wen-Long Liu
- , Mei-Zhen Zou
- & Xian-Zheng Zhang
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Article
| Open AccessActivation of NIX-mediated mitophagy by an interferon regulatory factor homologue of human herpesvirus
Impaired removal of damaged mitochondria by mitophagy can activate innate immune signaling, but impact on virus replication remains unclear. Here the authors show that viral IRF-1 of human herpesvirus 8 activates mitophagy via interaction with the mitophagy receptor NIX and that vIRF-1 induced mitophagy supports productive infection.
- Mai Tram Vo
- , Barbara J. Smith
- & Young Bong Choi
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Article
| Open AccessNQO1 targeting prodrug triggers innate sensing to overcome checkpoint blockade resistance
Improper innate sensing within the tumor microenvironment limits immunotherapy success. Here, the authors show that targeting NQO1 triggers immunogenic innate sensing to reactivate T cells and overcome immune checkpoint blockade resistance.
- Xiaoguang Li
- , Zhida Liu
- & Yang-Xin Fu
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Article
| Open AccessWhole-genome landscape of mucosal melanoma reveals diverse drivers and therapeutic targets
Mucosal melanomas are challenging to treat partly because so little is known about the genetic drivers underpinning them. Here, the authors perform a genomic landscape analysis of samples collected from three continents, revealing a potential role for CDK4/6 or MEK inhibition in the treatment of the disease.
- Felicity Newell
- , Yan Kong
- & Richard A. Scolyer
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Article
| Open AccessMulticenter study demonstrates radiomic features derived from magnetic resonance perfusion images identify pseudoprogression in glioblastoma
MRI scans of glioblastoma patients can be misleading and some patients appear to show features of progressive disease although they respond to treatment. Here, the authors use MRI images of progressive disease or pseudoprogression and build a classifier using machine learning to distinguish the two.
- Nabil Elshafeey
- , Aikaterini Kotrotsou
- & Rivka R. Colen
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Article
| Open AccessPRKCSH contributes to tumorigenesis by selective boosting of IRE1 signaling pathway
Cancer cells utilise the unfolded protein response (UPR) to adapt to environmental and ER stress. Here, the authors show that the glycosidase II beta subunit, PRKSCH, protects cancer cells from ER stress, by interacting with IRE1α and activating the IRE1α-XBP1 branch of the UPR.
- Gu-Choul Shin
- , Sung Ung Moon
- & Kyun-Hwan Kim
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Article
| Open AccessGenomic signatures reveal DNA damage response deficiency in colorectal cancer brain metastases
The development of brain metastases is a lethal yet poorly understood event in the evolution of many cancers. Here, the authors perform whole-genome and whole-exome sequencing on matched normal, primary and metastatic tissue samples to explore the genomic features of brain metastases in colorectal cancer.
- Jing Sun
- , Cheng Wang
- & Yanhong Gu
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Article
| Open AccessInactivating mutations and X-ray crystal structure of the tumor suppressor OPCML reveal cancer-associated functions
OPCML is a tumour suppressor gene that is epigenetically silenced in ovarian cancer and is somatically mutated in various cancers. Here, the authors solve the X-ray crystal structure of OPCML and model clinically relevant mutations that could contribute to tumorigenesis.
- James R. Birtley
- , Mohammad Alomary
- & Hani Gabra
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Article
| Open AccessSuper-resolution microscopy reveals ultra-low CD19 expression on myeloma cells that triggers elimination by CD19 CAR-T
CD19 CAR-T cells have achieved some success in treating myeloma patients despite the limited detection of the CD19 antigen. Here, the authors show using dSTORM that 10/14 myeloma samples studied express ultra-low levels of CD19, which are sufficient for engaging CAR-T cells in vitro.
- Thomas Nerreter
- , Sebastian Letschert
- & Michael Hudecek
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Article
| Open AccessBRCA2 abrogation triggers innate immune responses potentiated by treatment with PARP inhibitors
BRCA2 plays important roles in cell physiology by promoting DNA replication and DNA double-strand breaks repair. Here the authors, reveal the impact of BRCA2 depletion on the cell transcriptional program with activation of the innate immune response that is potentiated by PARP inhibitor treatments.
- Timo Reisländer
- , Emilia Puig Lombardi
- & Madalena Tarsounas
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Article
| Open AccessThe genomic landscape of Epstein-Barr virus-associated pulmonary lymphoepithelioma-like carcinoma
The rare lung cancer subtype pulmonary lymphoepithelioma-like carcinoma is linked to Epstein-Barr virus infection. Here, the authors provide a mutational landscape for this cancer, showing a low burden of somatic mutations and high prevalence of copy number variations.
- Shaodong Hong
- , Dongbing Liu
- & Li Zhang
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Article
| Open AccessMembrane protein-regulated networks across human cancers
Membrane proteins have been implicated in cancers, but studying the downstream effects of their perturbation remains challenging. Here, the authors map the membrane protein-regulated network of 15 cancers, a resource for prognostic biomarker development and druggable target identification.
- Chun-Yu Lin
- , Chia-Hwa Lee
- & Jinn-Moon Yang
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Article
| Open AccessLandscape of transcriptomic interactions between breast cancer and its microenvironment
The transcriptomic profile of tumour-adjacent cells provides important information about tumour context but its clinical utility is unclear. Here, in breast cancer, Fox et al. show that the mRNA abundances of tumour and tumour-adjacent cells hold prognostic information.
- Natalie S. Fox
- , Syed Haider
- & Paul C. Boutros
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Article
| Open AccessPatient-specific cancer genes contribute to recurrently perturbed pathways and establish therapeutic vulnerabilities in esophageal adenocarcinoma
Identifying driver genes in unstable, heterogenous tumour types can be challenging. Here, Mourikis, Benedetti, Foxall and colleagues present a machine learning algorithm to tackle this problem in esophageal adenocarcinoma.
- Thanos P. Mourikis
- , Lorena Benedetti
- & Francesca D. Ciccarelli
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Article
| Open AccessAssociation of imputed prostate cancer transcriptome with disease risk reveals novel mechanisms
In prostate cancer, investigating aberrant gene expression may shed light on disease etiology. Here, the authors imputed expression transcriptome-wide for 233,955 European ancestry men, discovering and replicating the associations between prostatic expression for select genes and prostate cancer risk, including the highly prevalent gene fusion partner TMPRSS2. The authors furthermore integrate diverse functional genomic datasets to interpret the epigenetic mechanisms by which the implicated risk variants and genes modulate disease risk.
- Nima C. Emami
- , Linda Kachuri
- & John S. Witte
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Article
| Open AccessBlockade of leukemia inhibitory factor as a therapeutic approach to KRAS driven pancreatic cancer
KRAS mutations are frequent in pancreatic ductal adenocarcinoma, leading to bad prognosis and resistance to targeted therapies. Here, the authors show that LIF expression is specifically induced by KRAS and constitutes a potential target to treat these KRAS-mutated cancers.
- Man-Tzu Wang
- , Nicole Fer
- & Frank McCormick
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Article
| Open AccessRegulation of tumor angiogenesis and mesenchymal–endothelial transition by p38α through TGF-β and JNK signaling
Mesenchymal cells contribute to tumor angiogenesis by regulating proliferation and migration of endothelial cells. Here, the authors show that mesenchymal stem cells also have the ability to acquire an endothelial phenotype upon TGF-β stimulation via the downstream kinase JNK, and that p38α negatively regulates this process.
- Raquel Batlle
- , Eva Andrés
- & Angel R. Nebreda
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Article
| Open AccessEradication of unresectable liver metastasis through induction of tumour specific energy depletion
Treatment of liver metastasis in cancer patients is associated with severe side effects. Here, the authors develop nucleus and mitochondria targeted nanoparticles, conjugated via a cathepsin B sensitive peptide to selectively target liver metastatic cells.
- Da Huo
- , Jianfeng Zhu
- & Yong Hu
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Article
| Open AccessActivation of STAT3 signaling is mediated by TFF1 silencing in gastric neoplasia
Trefoil factor 1 (TFF1) is a protein secreted by the gastric mucosa that protects against gastric tumourigenesis. Here, the authors show that TFF1 inhibits the oncogenic inflammatory response and IL-6-mediated STAT3 activation by interfering with the binding of IL6 to its receptor IL6Rα.
- Mohammed Soutto
- , Zheng Chen
- & Wael El-Rifai
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Comment
| Open AccessUntangling the evolutionary roots of lung cancer
The genomic and host factors that drive the progression of pre-invasive lesions in non-small cell lung cancer are poorly understood. Studying these factors can advance our knowledge of lung cancer biology, aid in the development of better screening strategies and improve patient outcomes.
- Siddhartha Devarakonda
- & Ramaswamy Govindan
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