Featured
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Article
| Open AccessSialyl Lewisx-P-selectin cascade mediates tumor–mesothelial adhesion in ascitic fluid shear flow
Tumor cell in the peritoneum are often exposed to shear forces generated by ascitic flow during metastasis. Here, the authors show that metastatic cancer stem cells tether more and roll slower than the non-metastatic counterparts, and that sialyl-Lewisx -P-selectin axis mediates peritoneal metastasis.
- Shan-Shan Li
- , Carman K. M. Ip
- & Alice S. T. Wong
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Article
| Open AccessFlexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP
Diagnostic filtering is an important step to analyze the functional and clinical significance of the large number of genetic variants identified from next-generation genome sequencing data. Here, the authors develop a flexible and scalable system for diagnostic filtering of genetic variants using G2P with Ensembl VEP.
- Anja Thormann
- , Mihail Halachev
- & David R. FitzPatrick
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Article
| Open AccessThe oncolytic virus Delta-24-RGD elicits an antitumor effect in pediatric glioma and DIPG mouse models
The oncolytic virus Delta-24-RGD is in clinical trial for adult glioma. Here, the authors show that this virus elicits an immune response in mouse models of pediatric high-grade glioma and diffuse pontine intrinsic glioma, resulting in improved survival.
- Naiara Martínez-Vélez
- , Marc Garcia-Moure
- & Marta M. Alonso
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Article
| Open AccessThe FANCM-BLM-TOP3A-RMI complex suppresses alternative lengthening of telomeres (ALT)
ALT telomeres experience DNA damage that may drive recombination-based telomere elongation. Here, the authors reveal that FANCM plays a critical role in the suppression of ALT activity through its interaction with the BTR (BLM-TOP3A-RMI) complex.
- Robert Lu
- , Julienne J. O’Rourke
- & Hilda A. Pickett
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Article
| Open AccessSORLA regulates endosomal trafficking and oncogenic fitness of HER2
The EGF receptor HER2 is an oncogene protein thought to reside at the plasma membrane, but its endosomal trafficking is currently unclear. Here, the authors report that HER2 is endocytosed and that sortillin-related receptor 1 (SORLA) promotes endosomal HER2 recycling and HER2 oncogenic signalling.
- Mika Pietilä
- , Pranshu Sahgal
- & Johanna Ivaska
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Article
| Open AccessFANCM limits ALT activity by restricting telomeric replication stress induced by deregulated BLM and R-loops
In cancer cells, telomeres can be elongated through homology directed-repair pathways in a process known as Alternative Lengthening of Telomeres (ALT). Here, the authors reveal that FANCM regulates ALT activity and ALT cell proliferation by limiting the activity of uncontrolled BLM and telomeric R-loops.
- Bruno Silva
- , Richard Pentz
- & Claus M. Azzalin
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Article
| Open AccessCollective cell migration and metastases induced by an epithelial-to-mesenchymal transition in Drosophila intestinal tumors
Modelling and visualizing tumor metastasis in Drosophila has been a challenge. Here, the authors show that constitutive expression of Sna in primary adult Drosophila intestinal tumors drives EMT and dissemination of tumor cells, induces collective cell migration and formation of polyclonal metastases.
- Kyra Campbell
- , Fabrizio Rossi
- & Andreu Casali
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Article
| Open AccessTransforming activity of an oncoprotein-encoding circular RNA from human papillomavirus
The authors identify circular RNAs (circRNA) from human papillomavirus and show that circRNA-encoded E7 contributes to cancer cell growth in vitro and in tumor xenografts. Furthermore, circE7 is present in TCGA RNA-Seq data from HPV-positive cancers.
- Jiawei Zhao
- , Eunice E. Lee
- & Richard C. Wang
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Article
| Open AccessA toll-like receptor agonist mimicking microbial signal to generate tumor-suppressive macrophages
Turning tumour promoting macrophages into an anti-tumour phenotype is an attractive therapeutic strategy. Here, the authors develop a polysaccharide-based structure that mimicks pathogen-associated molecular patterns and, by activating the toll-like receptors on macrophage surface, promotes a safe anti-tumour immune response in mouse models.
- Yanxian Feng
- , Ruoyu Mu
- & Chunming Wang
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Article
| Open AccessLNK suppresses interferon signaling in melanoma
LNK is a tumor suppressor in hematopoietic cancers, but its function in melanoma is unclear. Here, the authors show that the overexpression of LNK in melanomas correlate with hyperactive signaling of the RAS-RAF-MEK pathway and LNK enhances melanoma growth and survival and immune evasion by inhibiting IFN signalling.
- Ling-Wen Ding
- , Qiao-Yang Sun
- & H. Phillip Koeffler
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Article
| Open AccessKrt5+/Krt15+ foregut basal progenitors give rise to cyclooxygenase-2-dependent tumours in response to gastric acid stress
Cellular extrinsic environmental factors contribute to tumour development. Here, the authors show that gastric acid stress stimulates tumour formation from a defined tumour-competent Krt5 + /Krt15 + foregut basal progenitor cell population.
- Hyeongsun Moon
- , Jerry Zhu
- & Andrew C. White
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Article
| Open AccessOptimization of 4-1BB antibody for cancer immunotherapy by balancing agonistic strength with FcγR affinity
Agonistic 4-1BB antibodies developed for cancer immunotherapy have suffered from either hepatotoxicity or insufficient anti-cancer activity. Here the authors determine the contribution of FcγR binding and agonistic strength to these outcomes, and engineer a 4-1BB antibody with potent anti-tumor effect and no liver toxicity in mice.
- Xinyue Qi
- , Fanlin Li
- & Xuanming Yang
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Article
| Open AccessMethylation and PTEN activation in dental pulp mesenchymal stem cells promotes osteogenesis and reduces oncogenesis
Mesenchymal stem cells derived from dental pulp (DP-MSCs) differ in oncogenesic and developmental potential compared to those from bone marrow. Here, the authors show that decreased DNA methylation and histone H3K9Me2 enrichment along with higher PTEN activation in DP-MSCs promotes osteogenesis and reduces oncogenesis.
- Wen-Ching Shen
- , Yung-Chih Lai
- & Shih-Chieh Hung
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Article
| Open AccessAlbumin tailoring fluorescence and photothermal conversion effect of near-infrared-II fluorophore with aggregation-induced emission characteristics
There is a balance between the fluorescence and photothermal properties of fluorescent molecules. Here, the authors report on an NIR-II fluorophore which binds with human serum albumin changing the equilibrium, increasing the photothermal efficiency, and demonstrate application of this for tumour ablation.
- Shuai Gao
- , Guoguang Wei
- & Wei Lu
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Article
| Open AccessALPK1 hotspot mutation as a driver of human spiradenoma and spiradenocarcinoma
Spiradenoma and cylindroma are skin adnexal tumors that can behave aggressively and undergo malignant transformation. Here, the authors genetically assess a cohort of these adnexal tumours, highlighting recurrent ALPK1 mutations and revealing the genomic landscape of these rare tumours.
- Mamunur Rashid
- , Michiel van der Horst
- & David J. Adams
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Article
| Open AccessTargeting lonidamine to mitochondria mitigates lung tumorigenesis and brain metastasis
Brain metastases are a major reason for lung cancer mortality. Here, the authors modify lonidamine to target mitochondria, and show its therapeutic efficacy in inhibiting lung cancer brain metastasis by inducing autophagic cell death in cancer cells.
- Gang Cheng
- , Qi Zhang
- & Ming You
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Article
| Open AccessChromatin dysregulation and DNA methylation at transcription start sites associated with transcriptional repression in cancers
In tumours aberrant epigenetic modifications can alter the transcriptional state. Here, the authors identify a common tumour-specific shift to transcriptional repression associated with DNA methylation and chromatin dysregulation at the transcription start site.
- Mizuo Ando
- , Yuki Saito
- & Joseph A. Califano
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Article
| Open AccessA high-throughput screen indicates gemcitabine and JAK inhibitors may be useful for treating pediatric AML
Pediatric AML is traditionally treated with chemotherapy and stem cell transplant but some subsets of patients have a poor response to therapy. Here, the authors perform a high throughput screen and identify several FDA approved drugs that might be useful in treating this disease.
- Christina D. Drenberg
- , Anang Shelat
- & Sharyn D. Baker
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Article
| Open AccessFunctional linkage of gene fusions to cancer cell fitness assessed by pharmacological and CRISPR-Cas9 screening
Gene fusions are observed in many cancers but their link to tumour fitness is largely unknown. Here, transcriptomic analysis combined with pharmacological and CRISPR-Cas9 screening of cancer cell lines was used to evaluate the functional linkage between fusions and tumour fitness.
- Gabriele Picco
- , Elisabeth D. Chen
- & Mathew J. Garnett
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Article
| Open AccessMEK inhibitors activate Wnt signalling and induce stem cell plasticity in colorectal cancer
Wnt signaling is necessary for colorectal cancer tumorigenesis and stem cell maintenance. Here, the authors identify MEK1/2 inhibitors as potent activators of Wnt/β-catenin signalling and show that clinically approved MEK inhibitors inadvertently induce stem cell plasticity in colorectal cancer
- Tianzuo Zhan
- , Giulia Ambrosi
- & Michael Boutros
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Article
| Open AccessEvaluating cell lines as models for metastatic breast cancer through integrative analysis of genomic data
While cell lines and organoids are extensively used to study cancer, how closely they resemble the disease in patients remains unclear. Here, Liu et al. shed light on this issue by comparing the genomic and transcriptomic profiles of different breast cancer cell lines and organoids to data from patient-derived breast cancer metastases.
- Ke Liu
- , Patrick A. Newbury
- & Bin Chen
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Article
| Open AccessHydro-Seq enables contamination-free high-throughput single-cell RNA-sequencing for circulating tumor cells
Transcriptome analysis of circulating tumor cells (CTCs) provides insights into monitoring target therapeutics and underlying tumor metastasis. Here the authors present Hydro-Seq, a contamination-free high-throughput hydrodynamic scRNA-seq barcoding technique for rare CTCs.
- Yu-Heng Cheng
- , Yu-Chih Chen
- & Euisik Yoon
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Article
| Open AccessAssociation analyses identify 31 new risk loci for colorectal cancer susceptibility
In colorectal cancer (CRC), finding loci associated with risk may give insight into disease aetiology. Here, the authors report a genome-wide association analysis in Europeans of 34,627 CRC cases and 71,379 controls, and find 31 new risk loci and 17 new risk SNPs at previously reported loci.
- Philip J. Law
- , Maria Timofeeva
- & Malcolm G. Dunlop
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Article
| Open AccessJNK1/2 represses Lkb1-deficiency-induced lung squamous cell carcinoma progression
LKB1 is frequently mutated in lung squamous cell carcinomas. Here, the authors show that sole LKB1 depletion is sufficient to drive the development of this cancer, where downstream defective MKK7-JNK1/2 signalling activates the ∆Np63/p63 pathway to induce subsequent epithelial cells transformation and tumour progression.
- Jian Liu
- , Tianyuan Wang
- & Francesco J. DeMayo
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Article
| Open AccessNucleoporin Nup155 is part of the p53 network in liver cancer
The nuclear pore complex (NPC) is known to regulate p53 signaling and this has mainly been linked to peripheral NPC subunits. Here the authors show that Nup155 from the NPC inner ring regulates the p53 pathway by controlling p21 translation while also being a target of p53-mediated repression.
- Kerstin Holzer
- , Alessandro Ori
- & Stephan Singer
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Article
| Open AccessCollagen-rich airway smooth muscle cells are a metastatic niche for tumor colonization in the lung
Collagen is a dynamic component of both the tumor and metastatic niche. Here, the authors show that airway smooth muscle cells are a collagen III rich niche bladder cancer cells expressing CD167a, and Stat3 is a downstream target for abrogating these collagen III/CD167a-driven metastatic foci.
- Yu-Cheng Lee
- , Antonina V. Kurtova
- & Keith Syson Chan
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Article
| Open AccessAn integrated stress response via PKR suppresses HER2+ cancers and improves trastuzumab therapy
The HER2 monoclonal antibody, Trastuzumab, is the current standard treatment for HER2+ cancers but resistance to therapy occurs. Here, the authors show that activation of the PKR/eIF2α-P pathway exhibits anti-tumor effects in HER2+ cancer and is required for the response to Trastuzumab.
- Cedric Darini
- , Nour Ghaddar
- & Antonis E. Koromilas
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Article
| Open AccessPFA ependymoma-associated protein EZHIP inhibits PRC2 activity through a H3 K27M-like mechanism
PFA tumours express high levels of EZHIP (also known as CXORF67). Here the authors find that EZHIP directly interacts with the active site of EZH2 and is a competitive inhibitor of PRC2 and that EZHIP gives rise to H3K27me3 genomic profile similar to the K27M oncohistone.
- Siddhant U. Jain
- , Truman J. Do
- & Peter W. Lewis
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Article
| Open AccessSREBP1 drives Keratin-80-dependent cytoskeletal changes and invasive behavior in endocrine-resistant ERα breast cancer
ERα breast cancer can relapse to metastatic disease following endocrine therapy. Here, the authors find that when aromatase inhibitor treatment resistance develops, epigenomic reprogramming drives Keratin-80 upregulation via SREBP1, and promotes cytoskeletal rearrangements that drive cancer cell invasion.
- Ylenia Perone
- , Aaron J. Farrugia
- & Luca Magnani
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Article
| Open AccessRibosome biogenesis during cell cycle arrest fuels EMT in development and disease
Ribosomal DNA transcription is essential for cell growth and division. Here, the authors show that EMT is accompanied by Snail binding to rDNA operons and Rictor association with nucleoli to fuel an induction of ribosome biogenesis during G1/S cell cycle arrest and inhibition of ribosome biogenesis hampers EMT, differentiates primary tumors and reduces metastasis.
- Varsha Prakash
- , Brittany B. Carson
- & C. Theresa Vincent
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Article
| Open AccessSynthetic TRuC receptors engaging the complete T cell receptor for potent anti-tumor response
Supraphysiological T cell activation by chimeric antigen receptor (CAR) contributes to T cell exhaustion and adverse events in CAR T cell therapies. Here the authors engineer a synthetic antigen receptor that integrates into the endogenous TCR complex, preserving natural regulatory circuits and achieving improved performance in mouse tumor models.
- Patrick A. Baeuerle
- , Jian Ding
- & Robert Hofmeister
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Article
| Open AccessRETRACTED ARTICLE: RNA m6A methylation regulates the epithelial mesenchymal transition of cancer cells and translation of Snail
RNA m6A methylation is known to be dysregulated in many cancers. Here, the authors show that m6A methylation of Snail mRNA regulates its translation with potential effects on epithelial mesenchymal transition.
- Xinyao Lin
- , Guoshi Chai
- & Hongsheng Wang
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Article
| Open AccessThe transcription factor CBFB suppresses breast cancer through orchestrating translation and transcription
CBFB is highly mutated in breast cancers and is known to interact with RUNX proteins to regulate transcription. Here, the authors describe a non-canonical role of CBFB in translation regulation in which it binds to mRNAs through hnRNPK, facilitating translation by eIF4B.
- Navdeep Malik
- , Hualong Yan
- & Jing Huang
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Article
| Open AccessLnc-TALC promotes O6-methylguanine-DNA methyltransferase expression via regulating the c-Met pathway by competitively binding with miR-20b-3p
Temozolomide resistance in glioblastoma is associated with MGMT overexpression. Here, the authors identify a lncRNA that is a competitive endogenous RNA for miR-20b-3p, which causes c-Met activation to modulate acetylation of histone H3 on MGMT promoter through Stat3/p300 complex to increase MGMT expression and temozolomide resistance.
- Pengfei Wu
- , Jinquan Cai
- & Chuanlu Jiang
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Article
| Open AccessClonal evolution patterns in acute myeloid leukemia with NPM1 mutation
NPM1 gene mutation is a founding event in acute myeloid leukaemia. Here, the authors find that at relapse, some patients lose the NPM1 mutation and show distinct mutational and gene expression patterns, highlighting a potential route for relapse.
- Sibylle Cocciardi
- , Anna Dolnik
- & Konstanze Döhner
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Article
| Open AccessWhole-genome sequencing reveals novel tandem-duplication hotspots and a prognostic mutational signature in gastric cancer
Structural variations in gastric cancer impact progression. Here, the authors perform whole-genome sequencing on 168 gastric cancer patients and identified tandem-duplications of super-enhancer ZFP36L2 in 10% of gastric cancer, and mutational signatures in tumors with cadherin 1 mutations that associated with poor prognoses.
- Rui Xing
- , Yong Zhou
- & Youyong Lu
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Article
| Open AccessCheckpoint blockade and nanosonosensitizer-augmented noninvasive sonodynamic therapy combination reduces tumour growth and metastases in mice
Immunotherapy for the treatment of cancer can be complicated by side effects and poor efficacy. Here, the authors use a nanoparticle-based approach in combination with a TLR7 agonist and sonodynamic therapy, and find that when used together with anti-PD-L1, tumour formation and metastases are impacted.
- Wenwen Yue
- , Liang Chen
- & Yu Chen
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Article
| Open AccessMEK1/2 inhibitor withdrawal reverses acquired resistance driven by BRAFV600E amplification whereas KRASG13D amplification promotes EMT-chemoresistance
Colorectal cancer cells can acquire resistance to MEK inhibition due to BRAF or KRAS amplification. Here, the authors show that while MEK inhibitor withdrawal in BRAF mutant cells restores sensitivity to the inhibitor through the loss of BRAF amplification mediated by a p57-dependent mechanism, drug withdrawal from KRAS mutant cells does not restore sensitivity but results in EMT and chemoresistance.
- Matthew J. Sale
- , Kathryn Balmanno
- & Simon J. Cook
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Article
| Open AccessInhibition of MYC by the SMARCB1 tumor suppressor
SMARCB1/SNF5 is a tumour suppressor and component of the SWI/SNF chromatin remodeler. Here the authors show that, independent of chromatin remodelling activities, SNF5 acts to inhibit the pro-tumorigenic transcriptional program of MYC via control of RNA polymerase pause release at MYC target genes.
- April M. Weissmiller
- , Jing Wang
- & William P. Tansey
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Article
| Open AccessCapicua regulates neural stem cell proliferation and lineage specification through control of Ets factors
Although Capicua (Cic), a transcriptional repressor, is linked to cancer, little is known about its function in the non-diseased brain. Here, authors show that Cic is strongly expressed in astrocytic and neuronal lineage cells during development and regulates proliferation and lineage selection via de-repression of Ets transcription factors.
- Shiekh Tanveer Ahmad
- , Alexandra D. Rogers
- & Jennifer A. Chan
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Article
| Open AccessLncRNA EPR controls epithelial proliferation by coordinating Cdkn1a transcription and mRNA decay response to TGF-β
Several lncRNAs are regulated by TGF-β. Here the authors report that an intergenic lncRNA —EPR— is a component of the TGF-β signaling pathway and controls epithelial cell proliferation by altering transcription and mRNA decay of Cdkn1a. EPR overexpression restrains tumor growth of orthotopically transplanted mice.
- Martina Rossi
- , Gabriele Bucci
- & Roberto Gherzi
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Article
| Open AccessDNA-enabled rational design of fluorescence-Raman bimodal nanoprobes for cancer imaging and therapy
Currently available Raman scanners are limited in speed to acquire images of clinically relevant sizes in cancer imaging. Here, the authors developed a DNA based design principle for Raman-Fluorescence bimodal nanoparticles and demonstrate real-time, high precision image-guided tumor resections and photothermal ablation of cancer.
- Suchetan Pal
- , Angana Ray
- & Moritz F. Kircher
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Article
| Open AccessIn vivo rendezvous of small nucleic acid drugs with charge-matched block catiomers to target cancers
Nanoparticle delivery of siRNA has problems with penetration and off target accumulation. Here, the authors report on the development of Y-shaped block catiomers which dynamically wrap around siRNA; demonstrate increased circulation times and delivery into hard to reach brain and pancreas tumour models.
- Sumiyo Watanabe
- , Kotaro Hayashi
- & Kazunori Kataoka
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Article
| Open AccessExcessive miR-25-3p maturation via N6-methyladenosine stimulated by cigarette smoke promotes pancreatic cancer progression
Cigarette smoke induces microRNA dysregulation in cancers. Here, the authors show that cigarette smoke promotes the maturation of oncogenic primary miR-25 due to METTL3 hypomethylation, and mature miR-25 suppresses PH domain leucine-rich repeat protein phosphatase 2, resulting in oncogenic AKT activation in pancreatic cancer.
- Jialiang Zhang
- , Ruihong Bai
- & Dongxin Lin
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Article
| Open AccessMultiple myeloma immunoglobulin lambda translocations portend poor prognosis
Multiple myeloma is frequently characterised by translocation of genes next to the immunoglobulin heavy chain locus. In this study, the authors sequence a large cohort of high risk myeloma samples and find translocations of cMyc to the immunoglobulin heavy chain locus and this is associated with poor prognosis.
- Benjamin G. Barwick
- , Paola Neri
- & Lawrence H. Boise
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Article
| Open AccessPromotion of growth factor signaling as a critical function of β-catenin during HCC progression
Aberrant Wnt/b-catenin signaling is thought to be a major driver of hepatocellular carcinoma. Here, the authors show that β-Catenin is predominantly integrated within the AJ complex during the early stages of this cancer and enhance EGFR signaling to promote tumour survival.
- Eunsun Kim
- , Amanda Lisby
- & Patrick Viatour
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Article
| Open AccessYAP-independent mechanotransduction drives breast cancer progression
The transcriptional regulator YAP is regarded as the universal mechanotransducer, largely from 2D culture studies. Here the authors show that in breast cancer patient tissues and cells in 3D culture, mechanical signals are transduced independently of YAP, questioning YAP as a therapeutic target.
- Joanna Y. Lee
- , Jessica K. Chang
- & Ovijit Chaudhuri
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Article
| Open AccessImmunostimulatory nanomedicines synergize with checkpoint blockade immunotherapy to eradicate colorectal tumors
Nanoparticles can stimulate tumour microenvironment to promote anti-tumour immunity. Here, the authors show that the combination of delivering drugs by a nanoscale coordination polymer and anti-PD-L1 is synergistic in treating murine colorectal cancer.
- Xiaopin Duan
- , Christina Chan
- & Wenbin Lin
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Article
| Open AccessMolecular subtyping reveals immune alterations associated with progression of bronchial premalignant lesions
Bronchial premalignant lesions can potentially progress to lung squamous cell carcinoma. Here, the authors profile bronchial biopsies from high-risk smokers by RNA sequencing and identify four molecular subtypes of premalignant lesions and an immune molecular signature that associates with lesion progression.
- Jennifer E. Beane
- , Sarah A. Mazzilli
- & Avrum E. Spira
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