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Targeting tumor plasticity is theoretically possible through the modulation of the expression of <jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content>\u2010binding proteins which can affect many different compensatory mechanisms of the adaptive response of malignant cells to targeted therapies. Human antigen R (HuR) is a modulator of gene expression and a transacting factor in the <jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content>\u2010processing machinery used in the cell stress response, and is a potential target for reducing tumor plasticity. In this experiment, we exploit the inherent heterogeneous response of the A375 melanoma line to suboptimal <jats:styled-content style=\"fixed-case\">BRAF<\/jats:styled-content> inhibition as a model of immediate adaptive response. We first observe that HuR overexpression can prevent the heterogeneous response and thus the immediate paradoxical proliferation induced by low\u2010doses vemurafenib treatment. We then use single\u2010cell mass cytometry to characterize subpopulations, including those that paradoxically proliferate, based on their proliferation rate and the expression patterns of markers involved in the reversible adaptive resistance to <jats:styled-content style=\"fixed-case\">BRAF<\/jats:styled-content> inhibition and\/or recognized as HuR targets involved in cell cycle regulation. Under suboptimal <jats:styled-content style=\"fixed-case\">BRAF<\/jats:styled-content> inhibition, HuR overexpression affects these subpopulations and their expression pattern with contrasting responses depending on their proliferation rate: faster\u2010proliferating vemurafenib\u2010sensitive or \u2010resistant subpopulations showed higher death tendency and reduced size, and slower\u2010proliferating subpopulations showed an attenuated resistant expression response and their paradoxical proliferation was inhibited. These observations pave the way to new therapeutic strategies for preventing the heterogeneous response of tumors to targeted therapies.<\/jats:p>","DOI":"10.1002\/cam4.1091","type":"journal-article","created":{"date-parts":[[2017,6,2]],"date-time":"2017-06-02T02:12:39Z","timestamp":1496369559000},"page":"1652-1664","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Overexpression of the human antigen R suppresses the immediate paradoxical proliferation of melanoma cell subpopulations in response to suboptimal <scp>BRAF<\/scp> inhibition"],"prefix":"10.1002","volume":"6","author":[{"given":"Marylise","family":"Fernandez","sequence":"first","affiliation":[{"name":"Department of Pathology and Immunology University of Geneva  Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hedwig","family":"Sutterl\u00fcty\u2010Fall","sequence":"additional","affiliation":[{"name":"Institute of Cancer Research Medical University of Vienna  Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christoph","family":"Schw\u00e4rzler","sequence":"additional","affiliation":[{"name":"Flow Cytometry Core Facility Ecole Polytechnique F\u00e9d\u00e9rale de Lausanne  Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sylvain","family":"Lemeille","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology University of Geneva  Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wolf\u2010Henning","family":"Boehncke","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology University of Geneva  Switzerland"},{"name":"Division of Dermatology University Hospital of Geneva  Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4439-3443","authenticated-orcid":false,"given":"Rastine","family":"Merat","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology University of Geneva  Switzerland"},{"name":"Division of Dermatology University Hospital of Geneva  Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2017,6]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMsb1607705"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/jid.2009.177"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1177\/1758834015571111"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature09626"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature13121"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature13572"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/msb4100200"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0906940106"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.05.049"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature14267"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2011.06.007"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2011.06.008"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01532-08"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.4331\/wjbc.v4.i4.111"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.20.3.760-769.2000"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/wrna.4"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.326827"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI45021"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-14-0726"},{"key":"e_1_2_7_21_1","article-title":"Posttranslational control of HuR function","author":"Grammatikakis I.","year":"2016","journal-title":"WIREs RNA"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/12027"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.71.3.1842-1849.1997"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/cyto.a.22067"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1404656111"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep23328"},{"key":"e_1_2_7_27_1","first-page":"85","article-title":"Mass cytometry to decipher the mechanism of nongenetic drug resistance in cancer","volume":"377","author":"Fienberg H. 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