{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T21:06:13Z","timestamp":1772831173950,"version":"3.50.1"},"reference-count":44,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2019,10,8]],"date-time":"2019-10-08T00:00:00Z","timestamp":1570492800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004361","name":"Krebsliga Schweiz","doi-asserted-by":"publisher","award":["KFS-3772-08-2015"],"award-info":[{"award-number":["KFS-3772-08-2015"]}],"id":[{"id":"10.13039\/501100004361","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Malignant pleural mesothelioma (MPM) is a lethal cancer with limited treatment options. No targeted therapy has emerged yet. Here, we performed an integrated molecular characterization of patient tumors in the TCGA dataset, and discovered that endoplasmic reticulum (ER) stress and the adaptive unfolded protein response (UPR) signaling are characteristically deregulated in MPM. Consequently, pharmacological perturbation of ER stress\/UPR axis by HA15, an agent that induces persistent proteotoxic stress in the ER, selectively suppresses the viability of MPM cells including those refractory to standard chemotherapy. Mechanically, HA15 augments the already high basal level of ER stress in MPM cells, embarks pro-apoptotic malfunctional UPR and autophagy, which eventually induces cell death in MPM. Importantly, HA15 exerts anti-MPM effectiveness in a mouse model of patient-derived xenografts (PDX) without eliciting overt toxicity when compared to chemotherapy. Our results revealed that programs orchestrating ER stress\/UPR signaling represent therapeutic vulnerabilities in MPM and validate HA15 as a promising agent to treat patients with MPM, na\u00efve or resistant to chemotherapy.<\/jats:p>","DOI":"10.3390\/cancers11101502","type":"journal-article","created":{"date-parts":[[2019,10,9]],"date-time":"2019-10-09T03:14:33Z","timestamp":1570590873000},"page":"1502","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Endoplasmic Reticulum Stress Signaling as a Therapeutic Target in Malignant Pleural Mesothelioma"],"prefix":"10.3390","volume":"11","author":[{"given":"Duo","family":"Xu","sequence":"first","affiliation":[{"name":"Department of General Thoracic Surgery, Department for BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern, 3008 Bern, Switzerland"},{"name":"Graduate School for Cellular and Biomedical Sciences, University of Bern, 3008 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8732-5910","authenticated-orcid":false,"given":"Haitang","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of General Thoracic Surgery, Department for BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern, 3008 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhang","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of General Thoracic Surgery, Department for BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern, 3008 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5442-9791","authenticated-orcid":false,"given":"Sabina","family":"Berezowska","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University of Bern, 3008 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanyun","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of General Thoracic Surgery, Department for BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern, 3008 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4664-6029","authenticated-orcid":false,"given":"Shun-Qing","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of General Thoracic Surgery, Department for BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern, 3008 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3005-220X","authenticated-orcid":false,"given":"Thomas M.","family":"Marti","sequence":"additional","affiliation":[{"name":"Department of General Thoracic Surgery, Department for BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern, 3008 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sean R. R.","family":"Hall","sequence":"additional","affiliation":[{"name":"Department of General Thoracic Surgery, Department for BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern, 3008 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7203-3122","authenticated-orcid":false,"given":"Patrick","family":"Dorn","sequence":"additional","affiliation":[{"name":"Department of General Thoracic Surgery, Department for BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern, 3008 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gregor J.","family":"Kocher","sequence":"additional","affiliation":[{"name":"Department of General Thoracic Surgery, Department for BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern, 3008 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ralph A.","family":"Schmid","sequence":"additional","affiliation":[{"name":"Department of General Thoracic Surgery, Department for BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern, 3008 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ren-Wang","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of General Thoracic Surgery, Department for BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern, 3008 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,10,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1016\/j.jtho.2018.02.021","article-title":"Progress in the Management of Malignant Pleural Mesothelioma in 2017","volume":"13","author":"McCambridge","year":"2018","journal-title":"J. Thorac. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Berzenji, L., and Van Schil, P. (2018). Multimodality treatment of malignant pleural mesothelioma. F1000Research, 7.","DOI":"10.12688\/f1000research.15796.1"},{"key":"ref_3","unstructured":"Travis, W.D., Brambilla, E., Burke, A.P., Marx, A., and Nicholson, A.G. (2015). WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart, International Agency for Research on Cancer. [4th ed.]."},{"key":"ref_4","first-page":"182","article-title":"Advances in the diagnosis, treatment and prognosis of malignant pleural mesothelioma","volume":"3","author":"Zhang","year":"2015","journal-title":"Ann. Transl. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1183\/16000617.0063-2016","article-title":"Malignant pleural mesothelioma: An update on investigation, diagnosis and treatment","volume":"25","author":"Bibby","year":"2016","journal-title":"Eur. Respir. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1038\/bjc.2013.731","article-title":"An RNAi-based screen reveals PLK1, CDK1 and NDC80 as potential therapeutic targets in malignant pleural mesothelioma","volume":"110","author":"Linton","year":"2014","journal-title":"Br. J. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2636","DOI":"10.1200\/JCO.2003.11.136","article-title":"Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma","volume":"21","author":"Vogelzang","year":"2003","journal-title":"J. Clin. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1038\/ng.3520","article-title":"Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations","volume":"48","author":"Bueno","year":"2016","journal-title":"Nat. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1158\/2159-8290.CD-18-0804","article-title":"Integrative Molecular Characterization of Malignant Pleural Mesothelioma","volume":"8","author":"Hmeljak","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1158\/0008-5472.CAN-14-1008","article-title":"Whole-exome sequencing reveals frequent genetic alterations in BAP1, NF2, CDKN2A, and CUL1 in malignant pleural mesothelioma","volume":"75","author":"Guo","year":"2015","journal-title":"Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1038\/ng.855","article-title":"The nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma","volume":"43","author":"Bott","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.lungcan.2018.11.034","article-title":"Progress of malignant mesothelioma research in basic science: A review of the 14th international conference of the international mesothelioma interest group (iMig2018)","volume":"127","author":"Wu","year":"2019","journal-title":"Lung Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/j.trecan.2016.06.004","article-title":"Adaptive Stress Responses During Tumor Metastasis and Dormancy","volume":"2","author":"Senft","year":"2016","journal-title":"Trends Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1016\/j.cell.2016.12.004","article-title":"Tumorigenic and Immunosuppressive Effects of Endoplasmic Reticulum Stress in Cancer","volume":"168","author":"Bettigole","year":"2017","journal-title":"Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"17193","DOI":"10.3390\/ijms160817193","article-title":"Protein Folding and Mechanisms of Proteostasis","volume":"16","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"75","DOI":"10.15430\/JCP.2014.19.2.75","article-title":"Endoplasmic reticulum stress and cancer","volume":"19","author":"Yadav","year":"2014","journal-title":"J. Cancer Prev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.trecan.2016.03.007","article-title":"Endoplasmic Reticulum Stress and the Hallmarks of Cancer","volume":"2","author":"Urra","year":"2016","journal-title":"Trends Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3460","DOI":"10.1016\/j.bbamcr.2013.06.028","article-title":"ER stress-induced cell death mechanisms","volume":"1833","author":"Sano","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_19","first-page":"277","article-title":"The unfolded protein response as a target for cancer therapy","volume":"1846","author":"Nagelkerke","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2183","DOI":"10.1016\/j.bbamcr.2017.07.008","article-title":"Regulated proteolysis as an element of ER stress and autophagy: Implications for intestinal inflammation","volume":"1864","author":"Stengel","year":"2017","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1038\/nrneurol.2017.99","article-title":"ER stress and the unfolded protein response in neurodegeneration","volume":"13","author":"Hetz","year":"2017","journal-title":"Nat. Rev. Neurol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4946289","DOI":"10.1155\/2018\/4946289","article-title":"Targeting the Endoplasmic Reticulum Unfolded Protein Response to Counteract the Oxidative Stress-Induced Endothelial Dysfunction","volume":"2018","author":"Amodio","year":"2018","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"172553","DOI":"10.1016\/j.ejphar.2019.172553","article-title":"Endoplasmic reticulum stress: A master regulator of metabolic syndrome","volume":"860","author":"Mohan","year":"2019","journal-title":"Eur. J. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Logue, S.E., and Gorman, A.M. (2013). Current Concepts in ER Stress-Induced Apoptosis. J. Carcinog. Mutagen., 6.","DOI":"10.4172\/2157-2518.S6-002"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2656","DOI":"10.1172\/JCI26373","article-title":"Endoplasmic reticulum stress: Cell life and death decisions","volume":"115","author":"Xu","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1038\/s41416-018-0145-3","article-title":"Increased sensitivity to apoptosis upon endoplasmic reticulum stress-induced activation of the unfolded protein response in chemotherapy-resistant malignant pleural mesothelioma","volume":"119","author":"Xu","year":"2018","journal-title":"Br. J. Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e975089","DOI":"10.4161\/23723556.2014.975089","article-title":"Targeting the hallmarks of cancer with therapy-induced endoplasmic reticulum (ER) stress","volume":"2","author":"Garg","year":"2015","journal-title":"Mol. Cell Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1016\/j.ccell.2016.05.006","article-title":"Gr(i)p the ER to Stress Out Melanoma","volume":"29","author":"Xu","year":"2016","journal-title":"Cancer Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1016\/j.ccell.2016.04.013","article-title":"Compounds Triggering ER Stress Exert Anti-Melanoma Effects and Overcome BRAF Inhibitor Resistance","volume":"29","author":"Cerezo","year":"2016","journal-title":"Cancer Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.mce.2018.02.010","article-title":"The GRP78\/BiP inhibitor HA15 synergizes with mitotane action against adrenocortical carcinoma cells through convergent activation of ER stress pathways","volume":"474","author":"Ruggiero","year":"2018","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1827","DOI":"10.1016\/S0002-9440(10)62492-3","article-title":"Identification of novel candidate oncogenes and tumor suppressors in malignant pleural mesothelioma using large-scale transcriptional profiling","volume":"166","author":"Gordon","year":"2005","journal-title":"Am. J. Pathol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1184","DOI":"10.1093\/annonc\/mdu127","article-title":"Expression profiling stratifies mesothelioma tumors and signifies deregulation of spindle checkpoint pathway and microtubule network with therapeutic implications","volume":"25","author":"Suraokar","year":"2014","journal-title":"Ann. Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1038\/s41589-019-0326-2","article-title":"Pharmacological targeting of the unfolded protein response for disease intervention","volume":"15","author":"Hetz","year":"2019","journal-title":"Nat. Chem. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"15420","DOI":"10.1073\/pnas.1516362112","article-title":"Type I interferons mediate pancreatic toxicities of PERK inhibition","volume":"112","author":"Yu","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"C582","DOI":"10.1152\/ajpcell.00258.2014","article-title":"Cellular mechanisms of endoplasmic reticulum stress signaling in health and disease. 1. An overview","volume":"307","author":"Dufey","year":"2014","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.1016\/j.cell.2015.05.025","article-title":"ER Stress Sensor XBP1 Controls Anti-tumor Immunity by Disrupting Dendritic Cell Homeostasis","volume":"161","author":"Silberman","year":"2015","journal-title":"Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2626","DOI":"10.1172\/JCI74056","article-title":"ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R-mediated apoptosis","volume":"124","author":"Condamine","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1016\/j.immuni.2014.08.015","article-title":"The stress-response sensor chop regulates the function and accumulation of myeloid-derived suppressor cells in tumors","volume":"41","author":"Thevenot","year":"2014","journal-title":"Immunity"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1038\/35014014","article-title":"Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response","volume":"2","author":"Bertolotti","year":"2000","journal-title":"Nat. Cell Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1111\/j.1349-7006.2006.00184.x","article-title":"Establishment and characterization of four malignant pleural mesothelioma cell lines from Japanese patients","volume":"97","author":"Usami","year":"2006","journal-title":"Cancer Sci."},{"key":"ref_41","first-page":"5365","article-title":"Suppression of OCT4B enhances sensitivity of lung adenocarcinoma A549 cells to cisplatin via increased apoptosis","volume":"33","author":"Yazd","year":"2013","journal-title":"Anticancer Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s13287-016-0282-7","article-title":"Human lung-derived mesenchymal stem cell-conditioned medium exerts in vitro antitumor effects in malignant pleural mesothelioma cell lines","volume":"7","author":"Froment","year":"2016","journal-title":"Stem Cell Res. Ther."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e1824","DOI":"10.1038\/cddis.2015.195","article-title":"Blocking the epithelial-to-mesenchymal transition pathway abrogates resistance to anti-folate chemotherapy in lung cancer","volume":"6","author":"Liang","year":"2015","journal-title":"Cell Death Dis."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Liang, S.Q., Buhrer, E.D., Berezowska, S., Marti, T.M., Xu, D., Froment, L., Yang, H., Hall, S.R.R., Vassella, E., and Yang, Z. (2018). mTOR mediates a mechanism of resistance to chemotherapy and defines a rational combination strategy to treat KRAS-mutant lung cancer. Oncogene.","DOI":"10.1038\/s41388-018-0479-6"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/11\/10\/1502\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:28:18Z","timestamp":1760189298000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/11\/10\/1502"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,8]]},"references-count":44,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2019,10]]}},"alternative-id":["cancers11101502"],"URL":"https:\/\/doi.org\/10.3390\/cancers11101502","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,8]]}}}