000230722 001__ 230722
000230722 005__ 20180317093024.0
000230722 0247_ $$2doi$$a10.1002/cam4.1091
000230722 022__ $$a2045-7634
000230722 02470 $$2ISI$$a000405287700016
000230722 037__ $$aARTICLE
000230722 245__ $$aOverexpression of the human antigen R suppresses the immediate paradoxical proliferation of melanoma cell subpopulations in response to suboptimal BRAF inhibition
000230722 260__ $$aHoboken$$bWiley$$c2017
000230722 269__ $$a2017
000230722 300__ $$a13
000230722 336__ $$aJournal Articles
000230722 520__ $$aTumor plasticity and the heterogeneous response of melanoma cells to targeted therapies are major limits for the long-term efficacy of this line of therapy. Targeting tumor plasticity is theoretically possible through the modulation of the expression of RNA-binding 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 mRNA-processing 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 BRAF 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-doses vemurafenib treatment. We then use single-cell 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 BRAF inhibition and/or recognized as HuR targets involved in cell cycle regulation. Under suboptimal BRAF inhibition, HuR overexpression affects these subpopulations and their expression pattern with contrasting responses depending on their proliferation rate: faster-proliferating vemurafenib-sensitive or -resistant subpopulations showed higher death tendency and reduced size, and slower-proliferating 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.
000230722 6531_ $$aBRAF inhibitor
000230722 6531_ $$acell heterogeneity
000230722 6531_ $$amelanoma
000230722 6531_ $$aRNA-binding protein HuR
000230722 6531_ $$asingle-cell mass cytometry
000230722 6531_ $$atargeted therapy
000230722 700__ $$aFernandez, Marylise$$uUniv Geneva, Dept Pathol & Immunol, Geneva, Switzerland
000230722 700__ $$aSutterluety-Fall, Hedwig$$uMed Univ Vienna, Inst Canc Res, Vienna, Austria
000230722 700__ $$aSchwarzler, Christoph$$uEcole Polytech Fed Lausanne, Flow Cytometry Core Facil, Lausanne, Switzerland
000230722 700__ $$aLemeille, Sylvain$$uUniv Geneva, Dept Pathol & Immunol, Geneva, Switzerland
000230722 700__ $$aBoehncke, Wolf-Henning$$uUniv Geneva, Dept Pathol & Immunol, Geneva, Switzerland
000230722 700__ $$aMerat, Rastine$$uUniv Geneva, Dept Pathol & Immunol, Geneva, Switzerland
000230722 773__ $$j6$$k7$$q1652-1664$$tCancer Medicine
000230722 909CO $$ooai:infoscience.tind.io:230722$$particle
000230722 909C0 $$0252559$$pENT$$xU12833
000230722 937__ $$aEPFL-ARTICLE-230722
000230722 973__ $$aEPFL$$rREVIEWED$$sPUBLISHED
000230722 980__ $$aARTICLE