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Cancer Research

Livingstone Fultang, Laura D Gamble, Luciana Gneo, Andrea M Berry, Sharon A Egan, Fenna De Bie, Orli Yogev, Georgina L Eden, Sarah Booth, Samantha Brownhill, Ashley Vardon, Carmel M McConville, Paul N Cheng, Murray D Norris, Heather C Etchevers, Jayne Murray, David S Ziegler, Louis Chesler, Ronny Schmidt, Susan A Burchill, Michelle Haber, Carmela DeSanto, Francis Mussai
Neuroblastoma is the most common childhood solid tumor, yet the prognosis for high-risk disease remains poor. We demonstrate here that arginase 2 (ARG2) drives neuroblastoma cell proliferation via regulation of arginine metabolism. Targeting arginine metabolism, either by blocking cationic amino acid transporter 1 (CAT-1)-dependent arginine uptake in vitro or therapeutic depletion of arginine by pegylated-recombinant arginase BCT-100, significantly delayed tumor development and prolonged murine survival. Tumor cells polarized infiltrating-monocytes to a M1-macrophage phenotype, which released IL-1β and TNF-α in a RAC-alpha serine/threonine-protein kinase (AKT)-dependent manner...
December 13, 2018: Cancer Research
Paolo Neviani, Petra M Wise, Mariam Murtadha, Cathy W Liu, Chun-Hua Wu, Ambrose Y Jong, Robert C Seeger, Muller Fabbri
In neuroblastoma, the interplay between immune cells of the tumor microenvironment and cancer cells contributes to immune escape mechanisms and drug resistance. In this study, we show that NK cell-derived exosomes carrying the tumor suppressor microRNA (miR)-186 exhibit cytotoxicity against MYCN-amplified neuroblastoma cell lines. The cytotoxic potential of these exosomes was partly dependent upon expression of miR-186. MiR-186 was downregulated in high-risk neuroblastoma patients, and its low expression represented a poor prognostic factor that directly correlated with NK activation markers (i...
December 12, 2018: Cancer Research
Valsamo Anagnostou, Patrick M Forde, James R White, Noushin Niknafs, Carolyn Hruban, Jarushka Naidoo, Kristen A Marrone, I K Ashok Sivakumar, Daniel C Bruhm, Samuel Rosner, Jillian Phallen, Alessandro Leal, Vilmos Adleff, Kellie N Smith, Tricia R Cottrell, Lamia Rhymee, Doreen N Palsgrove, Christine L Hann, Benjamin Levy, Josephine Feliciano, Christos Georgiades, Franco Verde, Peter Illei, Qing Kay Li, Edward Gabrielson, Malcolm V Brock, James M Isbell, Jennifer L Sauter, Janis Taube, Robert B Scharpf, Rachel Karchin, Drew M Pardoll, Jamie E Chaft, Matthew D Hellmann, Julie R Brahmer, Victor E Velculescu
Despite the initial successes of immunotherapy, there is an urgent clinical need for molecular assays that identify patients more likely to respond. Here we report that ultrasensitive measures of circulating tumor DNA (ctDNA) and T cell expansion can be used to assess responses to immune checkpoint blockade in metastatic lung cancer patients (N=24). Patients with clinical response to therapy had a complete reduction in ctDNA levels after initiation of therapy whereas, non-responders had no significant changes or an increase in ctDNA levels...
December 12, 2018: Cancer Research
Go Oshima, Elizabeth C Poli, Michael J Bolt, Alexandre Chlenski, Martin Forde, Jessica M S Jutzy, Neha Biyani, Mitchell C Posner, Sean P Pitroda, Ralph R Weichselbaum, Nikolai N Khodarev
Expression of 14q32-encoded miRNA is a favorable prognostic factor in patients with metastatic cancer. In this study, we use genomic inhibition of DNA methylation through disruption of DNA methyltransferases DNMT1 and DNMT3B and pharmacologic inhibition with 5-Aza-2'-deoxycytidine (5-Aza-dC, Decitabine) to demonstrate that DNA methylation predominantly regulates expression of metastasis-suppressive miRNA in the 14q32 cluster. DNA demethylation facilitated CCCTC-binding factor (CTCF) recruitment to the Maternally Expressed Gene 3 differentially methylated region (MEG3-DMR), which acts as a cis-regulatory element for 14q32 miRNA expression...
December 11, 2018: Cancer Research
Elise Bonvin, Enrico Radaelli, Martin Bizet, Flavie Luciani, Emilie Calonne, Pascale Putmans, David Nittner, Nitesh Kumar Singh, Sara Francesca Santagostino, Valérie Petit, Lionel Larue, Jean Christophe Marine, François Fuks
Although numerous epigenetic aberrancies accumulate in melanoma, their contribution to initiation and progression remain unclear. The epigenetic mark 5-hydroxymethylcytosine (5hmC), generated through TET-mediated DNA modification, is now referred to as the sixth base of DNA and has recently been reported as a potential biomarker for multiple types of cancer. Loss of 5hmC is an epigenetic hallmark of melanoma, but whether a decrease in 5hmc levels contributes directly to pathogenesis or whether it merely results from disease-progression-associated epigenetic remodelling remains to be established...
December 11, 2018: Cancer Research
Dana S Neel, David V Allegakoen, Victor Olivas, Manasi K Mayekar, Golzar Hemmati, Nilanjana Chatterjee, Collin M Blakely, Caroline E McCoach, Julia K Rotow, Anh Le, Niki Karachaliou, Rafael Rosell, Jonathan W Riess, Robert Nichols, Robert C Doebele, Trever G Bivona
Chromosomal rearrangements involving receptor tyrosine kinases (RTK) are a clinically relevant oncogenic mechanism in human cancers. These chimeric oncoproteins often contain the C-terminal kinase domain of the RTK joined in cis to various N-terminal, non-kinase fusion partners. The functional role of the N-terminal fusion partner in RTK fusion oncoproteins is poorly understood. Here we show that distinct N-terminal fusion partners drive differential subcellular localization, which imparts distinct cell signaling and oncogenic properties of different, clinically-relevant ROS1 RTK fusion oncoproteins...
December 11, 2018: Cancer Research
Alexander S Chen, Joanna Wardwell-Ozgo, Nilang N Shah, Deidre Wright, Christina L Appin, Krishanthan Vigneswaran, Daniel J Brat, Harley I Kornblum, Renee D Read
Glioblastoma (GBM) and lower grade gliomas (LGG) are the most common primary malignant brain tumors and are resistant to current therapies. Genomic analyses reveal that signature genetic lesions in GBM and LGG include copy gain and amplification of chromosome 7, amplification, mutation, and overexpression of receptor tyrosine kinases (RTK) such as EGFR, and activating mutations in components of the PI-3 kinase (PI3K) pathway. In Drosophila melanogaster, constitutive co-activation of RTK and PI3K signaling in glial progenitor cells recapitulates key features of human gliomas...
December 10, 2018: Cancer Research
Sebastian A Wohlfeil, Verena Häfele, Bianca Dietsch, Kai Schledzewski, Manuel Winkler, Johanna Zierow, Thomas Leibing, Mona Malek Mohammadi, Joerg Heineke, Carsten Sticht, Victor Olsavszky, Philipp-Sebastian Koch, Cyrill Géraud, Sergij Goerdt
The interaction of tumor cells with organ-specific endothelial cells (EC) is an important step during metastatic progression. Notch signaling in organ-specific niches has been implicated in mediating opposing effects on organotropic metastasis to the lungs and the liver, respectively. In this study, we scrutinized the role of endothelial Notch activation during liver metastasis. To target hepatic EC (HEC), a novel EC subtype-specific Cre driver mouse was generated. Clec4g-Cretg/wt mice were crossed to Rosa26N1ICD IRES-GFP to enhance Notch signaling in HEC (NICDOE-HEC)...
December 10, 2018: Cancer Research
Marco Barazas, Alessia Gasparini, Yike Huang, Asli Küçükosmanoğlu, Stefano Annunziato, Peter Bouwman, Wendy Sol, Ariena Kersbergen, Natalie Proost, Renske de Korte-Grimmerink, Marieke van de Ven, Jos Jonkers, Gerben R Borst, Sven Rottenberg
The defect in homologous recombination (HR) found in BRCA1-associated cancers can be therapeutically exploited by treatment with DNA-damaging agents and poly (ADP-ribose) polymerase (PARP) inhibitors. We and others previously reported that BRCA1-deficient tumors are initially hypersensitive to the inhibition of topoisomerase I/II and PARP but acquire drug resistance through restoration of HR activity by the loss of end-resection antagonists of the 53BP1/RIF1/REV7/Shieldin/CST pathway. Here we identify radiotherapy as an acquired vulnerability of 53BP1;BRCA1-deficient cells in vitro and in vivo...
December 10, 2018: Cancer Research
Yuanzhuo Gu, Xiyang Wei, Yulin Sun, Hongjun Gao, Xin Zheng, Linda L Wong, Ling Jin, Niya Liu, Brenda Y Hernandez, Karolina Peplowska, Xiaohang Zhao, Qi-Min Zhan, Xin-Hua Feng, Zhao-You Tang, Junfang Ji
Various cancer stem cell (CSC) biomarkers have been identified for hepatocellular carcinoma (HCC), but little is known about the implications of heterogeneity and shared molecular networks within the CSC population. Through miRNA profile analysis in a HCC cohort (n=241) for five groups of CSC+ HCC tissues, i.e., EpCAM+, CD90+, CD133+, CD44+, and CD24+ HCC,we identified a 14-miRNA signature commonly altered among these five groups of CSC+ HCC. MiR-192-5p, the top ranked CSC-miRNA, was liver -abundant and -specific and markedly downregulated in all five groups of CSC+ HCC from two independent cohorts (n=613)...
December 7, 2018: Cancer Research
Walid Warda, Fabrice Larosa, Mathieu Neto Da Rocha, Rim Trad, Eric Deconinck, Ziad Fajloun, Cyril Faure, Denis Caillot, Marius Moldovan, Severine Valmary-Degano, Sabeha Biichle, Etienne Daguindau, Francine Garnache-Ottou, Sebastien Tabruyn, Olivier Adotévi, Marina Deschamps, Christophe Ferrand
Chronic myeloid leukemia (CML) is a chronic disease resulting in myeloid cell expansion through expression of the BCR-ABL1 fusion transcript. Tyrosine kinase inhibitors (TKI) have significantly increased survival of CML patients, and deep responders may consider stopping the treatment. However, more than 50% of patients relapse and restart TKI, subsequently suffering unknown toxicity. Because CML is a model immune system-sensitive disease, we hypothesize that chimeric antigen receptor (CAR) T cells targeting interleukin-1 receptor-associated protein (IL-1RAP) in quiescent CML stem cells may offer an opportunity for a permanent cure...
December 4, 2018: Cancer Research
Erikka Loftfield, Weiyin Zhou, Meredith Yeager, Stephen J Chanock, Neal D Freedman, Mitchell J Machiela
Mosaic loss of the Y chromosome (mLOY) in peripheral leukocytes is a somatic event in which a fraction of leukocytes have lost the entire Y chromosome. The frequency of mLOY increases with age and may reflect poor genomic maintenance as well as clonal imbalances in normal immune function, making mLOY an attractive candidate marker for cancer risk. Here we investigated the relationship between mLOY and incident cancer in a large sample of 207,603 cancer-free men from the UK Biobank in which 13,895 men developed an incident solid tumor during follow-up...
December 3, 2018: Cancer Research
Silvan Türkcan, Louise Kiru, Dominik J Naczynski, Laura S Sasportas, Guillem Pratx
The process by which tumor cells take up 18F-fluorodeoxyglucose (FDG) is heterogeneous and influenced by a multitude of factors. In mouse tumor grafts, the core of the tumor often presents lower FDG uptake than the periphery. Whether this pattern is caused by the intrinsic avidity of individual cells for FDG, the density of viable cells in the tumor, or the perfusion of the radiotracer remains unknown. In this study, we used radioluminescence microscopy to measure FDG uptake in single cells isolated from the core and periphery of the tumor and found that differences in FDG uptake persist on the level of single cells...
December 3, 2018: Cancer Research
U-Ging Lo, Rey-Chen Pong, Diane Yang, Leah Gandee, Elizabeth Hernandez, Andrew Dang, Chun-Jung Lin, John Santoyo, Shihong Ma, Rajni Sonavane, Jun Huang, Shu-Fen Tseng, Loredana Moro, Arnaldo A Arbini, Payal Kapur, Ganesh V Raj, Dalin He, Chih-Ho Lai, Ho Lin, Jer-Tsong Hsieh
Interferon-γ (IFNγ), a potent cytokine known to modulate tumor immunity and tumoricidal effects, is highly elevated in prostate cancer (PCa) patients after radiation. In this study, we demonstrate that IFNγ can induce epithelial-to-mesenchymal transition (EMT) in PCa cells via the JAK-STAT signaling pathway, leading to the transcription of IFN-stimulated genes (ISG) such as interferon-induced tetratricopeptide repeat 5 (IFIT5). We unveil a new function of IFIT5 complex in degrading precursor microRNAs (pre-miRNA) that include pre-miR-363 from the miR-106a-363 cluster as well as pre-miR-101 and pre-miR-128, who share a similar 5'-end structure with pre-miR-363...
November 30, 2018: Cancer Research
Eman L Dadashian, Erin M McAuley, Delong Liu, Arthur L Shaffer, Ryan M Young, Jessica R Iyer, Michael J Kruhlak, Louis M Staudt, Adrian Wiestner, Sarah E M Herman
Chronic lymphocytic leukemia (CLL) is a malignancy of mature B cells driven by B-cell receptor (BCR) signaling and activated primarily in the lymph node. The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib effectively inhibits BCR-dependent proliferation and survival signals and has emerged as a breakthrough therapy for CLL. However, complete remissions are uncommon and are achieved only after years of continuous therapy. We hypothesized that other signaling pathways that sustain CLL cell survival are only partially inhibited by ibrutinib...
November 29, 2018: Cancer Research
Cheng Zhang, Like Qu, Shenyi Lian, Lin Meng, Li Min, Jiafei Liu, Qian Song, Lin Shen, Chengchao Shou
The oncogenic phosphatase PRL-3 is highly expressed in metastatic colorectal cancer (CRC) but not in non-metastatic CRC or non-CRC metastatic cancers. Although the pro-invasive capacity of PRL-3 has been validated in multiple types of cancer, its impact on CRC progression and the underlying mechanisms remain poorly understood. Here we report that overexpressed PRL-3 stimulates G2/M arrest, chromosomal instability (CIN), self-renewal, and growth of CRC cells in xenograft models, while CRC cell proliferation is decreased...
November 29, 2018: Cancer Research
Ross A Stewart, Patrick G Pilié, Timothy A Yap
PARP inhibitors drive increased DNA damage, particularly in tumors with existing defects in DNA repair. This damage not only promotes immune priming through a range of molecular mechanisms, but also leads to adaptive upregulation of programmed death ligand 1 (PD-L1) expression. In this context, PARP inhibition and programmed cell death 1(PD-1)/PD-L1-targeting antibodies represent a rationale combination. In this review, we detail the basic and translational science underpinning this promising new combination, summarize available clinical data, and discuss the key questions that remain to be addressed during future development...
November 29, 2018: Cancer Research
Meredith A Morgan, Christine E Canman
Glioblastoma (GBM) is a highly aggressive form of cancer that is resistant to standard therapy with concurrent radiation and temozolomide, two agents that work by inducing DNA damage. An underlying cause of this resistance may be a subpopulation of cancer stem-like cells that display a heightened DNA damage response (DDR). Although this DDR represents an attractive therapeutic target for overcoming the resistance of GBMs to radiotherapy, until now, the cause of this DDR upregulation has not been understood...
November 29, 2018: Cancer Research
Arthur Dyer, Benjamin Schoeps, Sally Frost, Philip G Jakeman, Eleanor M Scott, Joshua Freedman, Leonard W Seymour
Tumour cells exhibiting the Warburg effect rely on aerobic glycolysis for ATP production and have a notable addiction to anaplerotic use of glutamine for macromolecular synthesis. This strategy maximises cellular biosynthetic potential while avoiding excessive depletion of NAD+, and provides an attractive anabolic environment for viral infection. Here we evaluate infection of highly permissive and poorly permissive cancer cells with wild type adenoviruses and the oncolytic chimeric adenovirus enadenotucirev (EnAd)...
November 28, 2018: Cancer Research
Melissa A Buckley, Nicholas T Woods, Jonathan P Tyrer, Gustavo Mendoza-Fandiño, Kate Lawrenson, Dennis J Hazelett, Hamed S Najafabadi, Anxhela Gjyshi, Renato S Carvalho, Paulo C Lyra, Simon G Coetzee, Howard C Shen, Ally W Yang, Madalene A Earp, Sean Yoder, Harvey Risch, Georgia Chenevix-Trench, Susan J Ramus, Catherine M Phelan, Gerhard A Coetzee, Houtan Noushmehr, Timothy R Hughes, Thomas A Sellers, Ellen L Goode, Paul D P Pharoah, Simon A Gayther, Alvaro N Monteiro
Genome-wide association studies have identified 40 ovarian cancer risk loci. However, the mechanisms underlying these associations remain elusive. In this study, we conducted a two-pronged approach to identify candidate causal SNPs and assess underlying biological mechanisms at chromosome 9p22.2, the first and most statistically significant associated locus for ovarian cancer susceptibility. Three transcriptional regulatory elements with allele-specific effects and a scaffold/matrix attachment region were characterized and through physical DNA interactions BNC2 was established as the most likely target gene...
November 28, 2018: Cancer Research
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