{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T11:12:57Z","timestamp":1790507577194,"version":"4.1.0"},"reference-count":51,"publisher":"American Society for Clinical Investigation","issue":"12","funder":[{"DOI":"10.13039\/501100023969","name":"hellenic thoracic society","doi-asserted-by":"crossref","award":["01.2016"],"award-info":[{"award-number":["01.2016"]}],"id":[{"id":"10.13039\/501100023969","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100023969","name":"hellenic thoracic society","doi-asserted-by":"crossref","award":["01.2016"],"award-info":[{"award-number":["01.2016"]}],"id":[{"id":"10.13039\/501100023969","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,6,18]]},"abstract":"<jats:p>\n                    Oxidative stress and inadequate redox homeostasis is crucial for tumor initiation and progression. MTH1 (NUDT1) enzyme prevents incorporation of oxidized dNTPs by sanitizing the deoxynucleoside triphosphate (dNTP) pool and is therefore vital for the survival of tumor cells. MTH1 inhibition has been found to inhibit the growth of several experimental tumors, but its role in mesothelioma progression remained elusive. Moreover, although MTH1 is nonessential to normal cells, its role in survival of host cells in tumor milieu, especially tumor endothelium, is unclear. We validated a clinically relevant MTH1 inhibitor (Karonudib) in mesothelioma treatment using human xenografts and syngeneic murine models. We show that MTH1 inhibition impedes mesothelioma progression and that inherent tumoral MTH1 levels are associated with a tumor\u2019s response. We also identified tumor endothelial cells as selective targets of Karonudib and propose a model of intercellular signaling among tumor cells and bystander tumor endothelium. We finally determined the major biological processes associated with elevated\n                    <jats:italic>MTH1<\/jats:italic>\n                    gene expression in human mesotheliomas.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.134885","type":"journal-article","created":{"date-parts":[[2020,6,17]],"date-time":"2020-06-17T11:01:33Z","timestamp":1592391693000},"source":"Crossref","is-referenced-by-count":13,"title":["MTH1 favors mesothelioma progression and mediates paracrine rescue of bystander endothelium from oxidative damage"],"prefix":"10.1172","volume":"5","author":[{"given":"Sophia F.","family":"Magkouta","sequence":"first","affiliation":[{"name":"\u201cMarianthi Simou Laboratory\u201d, 1st Department of Critical Care and Pulmonary Medicine, National and Kapodistrian University of Athens, School of Medicine, Evangelismos Hospital, Athens, Greece."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Apostolos G.","family":"Pappas","sequence":"additional","affiliation":[{"name":"\u201cMarianthi Simou Laboratory\u201d, 1st Department of Critical Care and Pulmonary Medicine, National and Kapodistrian University of Athens, School of Medicine, Evangelismos Hospital, Athens, Greece."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Photene C.","family":"Vaitsi","sequence":"additional","affiliation":[{"name":"\u201cMarianthi Simou Laboratory\u201d, 1st Department of Critical Care and Pulmonary Medicine, National and Kapodistrian University of Athens, School of Medicine, Evangelismos Hospital, Athens, Greece."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panagiotis C.","family":"Agioutantis","sequence":"additional","affiliation":[{"name":"\u201cMarianthi Simou Laboratory\u201d, 1st Department of Critical Care and Pulmonary Medicine, National and Kapodistrian University of Athens, School of Medicine, Evangelismos Hospital, Athens, Greece."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioannis S.","family":"Pateras","sequence":"additional","affiliation":[{"name":"Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National Kapodistrian University of Athens, Athens, Greece."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charalampos A.","family":"Moschos","sequence":"additional","affiliation":[{"name":"\u201cMarianthi Simou Laboratory\u201d, 1st Department of Critical Care and Pulmonary Medicine, National and Kapodistrian University of Athens, School of Medicine, Evangelismos Hospital, Athens, Greece."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianthi P.","family":"Iliopoulou","sequence":"additional","affiliation":[{"name":"\u201cMarianthi Simou Laboratory\u201d, 1st Department of Critical Care and Pulmonary Medicine, National and Kapodistrian University of Athens, School of Medicine, Evangelismos Hospital, Athens, Greece."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chrysavgi N.","family":"Kosti","sequence":"additional","affiliation":[{"name":"\u201cMarianthi Simou Laboratory\u201d, 1st Department of Critical Care and Pulmonary Medicine, National and Kapodistrian University of Athens, School of Medicine, Evangelismos Hospital, Athens, Greece."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heleni V.","family":"Loutrari","sequence":"additional","affiliation":[{"name":"\u201cMarianthi Simou Laboratory\u201d, 1st Department of Critical Care and Pulmonary Medicine, National and Kapodistrian University of Athens, School of Medicine, Evangelismos Hospital, Athens, Greece."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vassilis G.","family":"Gorgoulis","sequence":"additional","affiliation":[{"name":"Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National Kapodistrian University of Athens, Athens, Greece."},{"name":"Biomedical Research Foundation of the Academy of Athens, Athens, Greece."},{"name":"Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioannis T.","family":"Kalomenidis","sequence":"additional","affiliation":[{"name":"\u201cMarianthi Simou Laboratory\u201d, 1st Department of Critical Care and Pulmonary Medicine, National and Kapodistrian University of Athens, School of Medicine, Evangelismos Hospital, Athens, Greece."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2020,6,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2010.3685"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2009.2698"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/nature13181"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2014.195"},{"issue":"6","key":"B5","first-page":"2803","article-title":"Birth of MTH1 as a therapeutic target for glioblastoma: MTH1 is indispensable for gliomatumorigenesis","volume":"8","author":"Tu","year":"2016","journal-title":"Am J Transl Res"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdw429"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-018-0865-6"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-37316-w"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.canep.2019.03.014"},{"key":"B10","doi-asserted-by":"crossref","first-page":"v31","DOI":"10.1093\/annonc\/mdv199","article-title":"Malignant pleural mesothelioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up","volume":"26 Suppl 5","author":"Baas","year":"2015","journal-title":"Ann Oncol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.4253"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2846"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.17567"},{"key":"B14","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms13597","article-title":"MicroRNA regulation of endothelial TREX1 reprograms the tumour microenvironment","volume":"7","author":"Wilson","year":"2016","journal-title":"Nat Commun"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1002\/path.5097"},{"issue":"1","key":"B16","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.bbamcr.2015.10.022","article-title":"Characterization of the cell-free DNA released by cultured cancer cells","volume":"1863","author":"Bronkhorst","year":"2016","journal-title":"Biochim Biophys Acta"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-018-0250-9"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.17858"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1111\/brv.12413"},{"issue":"6","key":"B20","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1016\/j.bbamem.2014.01.020","article-title":"Regulation of innate immune responses by transmembrane interactions: lessons from the TLR family","volume":"1838","author":"Reuven","year":"2014","journal-title":"Biochim Biophys Acta"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2010.153"},{"issue":"2","key":"B22","doi-asserted-by":"crossref","DOI":"10.3390\/biomedicines6020058","article-title":"The Crosstalk of Endoplasmic Reticulum (ER) Stress Pathways with NF-\u03baB: Complex Mechanisms Relevant for Cancer, Inflammation and Infection","volume":"6","author":"Schmitz","year":"2018","journal-title":"Biomedicines"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2013.08.030"},{"key":"B24","doi-asserted-by":"crossref","DOI":"10.1177\/1758835919866960","article-title":"Karonudib is a promising anticancer therapy in hepatocellular carcinoma","volume":"11","author":"Hua","year":"2019","journal-title":"Ther Adv Med Oncol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2442"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1818322116"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/nature25432"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2019.04.011"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.mrfmmm.2011.09.005"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1172\/JCI27392"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-09-0383"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-13-1314"},{"key":"B33","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms15287","article-title":"Exosomes maintain cellular homeostasis by excreting harmful DNA from cells","volume":"8","author":"Takahashi","year":"2017","journal-title":"Nat Commun"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2017.54"},{"key":"B35","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms15728","article-title":"Small extracellular vesicles secreted from senescent cells promote cancer cell proliferation through EphA2","volume":"8","author":"Takasugi","year":"2017","journal-title":"Nat Commun"},{"key":"B36","doi-asserted-by":"crossref","DOI":"10.3389\/fonc.2015.00011","article-title":"Endoplasmic reticulum stress, genome damage, and cancer","volume":"5","author":"Dicks","year":"2015","journal-title":"Front Oncol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/nm.1947"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-07-2950"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-08-0060"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.25276"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-37130-4"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2018.1537427"},{"key":"B43","doi-asserted-by":"crossref","DOI":"10.1186\/1471-2105-12-323","article-title":"RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome","volume":"12","author":"Li","year":"2011","journal-title":"BMC Bioinformatics"},{"key":"B44","unstructured":"Broad Institute TCGA Genome Data Analysis Center. Analysis-ready standardized TCGA data from Broad GDAC Firehose 2016_01_28 run. Broad Institute of MIT and Harvard. https:\/\/doi.org\/10.7908\/C11G0KM9 Accessed June 1, 2020"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.neo.2017.05.002"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2010-11-3-r25"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp616"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gks042"},{"key":"B49","unstructured":"Blighe K. EnhancedVolcano: Publication-ready volcano plots with enhanced coloring and labeling. Package version 1.0.1. https:\/\/github.com\/kevinblighe\/EnhancedVolcano Accessed June 9, 2020"},{"issue":"2","key":"B50","article-title":"Analyzing and Visualizing Genomic Complexity for the Derivation of the Emergent Molecular Networks","volume":"4","author":"Koutsandreas","year":"2016","journal-title":"Int J Monit Surveill Technol Res"},{"issue":"3","key":"B51","doi-asserted-by":"crossref","DOI":"10.15252\/emmm.201707929","article-title":"Dual IRE1 RNase functions dictate glioblastoma development","volume":"10","author":"Lhomond","year":"2018","journal-title":"EMBO Mol Med"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/134885\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T12:13:42Z","timestamp":1779192822000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/134885"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,18]]},"references-count":51,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2020,6,18]]},"published-print":{"date-parts":[[2020,6,18]]}},"alternative-id":["10.1172\/jci.insight.134885"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.134885","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,18]]},"article-number":"e134885"}}