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Hypoxia-regulated gene expression explains differences between melanoma cell line-derived xenografts and patient-derived xenografts.

Journal article
Authors Joydeep Bhadury
Berglind Osk Einarsdottir
Agnieszka Podraza
Roger Olofsson Bagge
Ulrika Stierner
Lars Ny
Marcela Davila Lopez
Jonas A Nilsson
Published in Oncotarget
Volume 7
Issue 17
Pages 23801
ISSN 1949-2553
Publication year 2016
Published at Institute of Clinical Sciences, Department of Surgery
Institute of Clinical Sciences, Department of Oncology
Core Facilities, Bioinformatics
Pages 23801
Language en
Links dx.doi.org/10.18632/oncotarget.8181
Subject categories Cancer and Oncology, Surgery

Abstract

Cell line-derived xenografts (CDXs) are an integral part of drug efficacy testing during development of new pharmaceuticals against cancer but their accuracy in predicting clinical responses in patients have been debated. Patient-derived xenografts (PDXs) are thought to be more useful for predictive biomarker identification for targeted therapies, including in metastatic melanoma, due to their similarities to human disease. Here, tumor biopsies from fifteen patients and ten widely-used melanoma cell lines were transplanted into immunocompromised mice to generate PDXs and CDXs, respectively. Gene expression profiles generated from the tumors of these PDXs and CDXs clustered into distinct groups, despite similar mutational signatures. Hypoxia-induced gene signatures and overexpression of the hypoxia-regulated miRNA hsa-miR-210 characterized CDXs. Inhibition of hsa-miR-210 with decoys had little phenotypic effect in vitro but reduced sensitivity to MEK1/2 inhibition in vivo, suggesting down-regulation of this miRNA could result in development of resistance to MEK inhibitors.

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