Hypoxia-regulated gene expression explains differences between melanoma cell line-derived xenografts and patient-derived xenografts
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Joydeep Bhadury1, Berglind O. Einarsdottir1, Agnieszka Podraza1, Roger Olofsson Bagge1, Ulrika Stierner2, Lars Ny2, Marcela Dávila López3, Jonas A. Nilsson1
1Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden
2Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden
3The Bioinformatics Core Facility at the University of Gothenburg, Gothenburg, Sweden
Joydeep Bhadury, e-mail: email@example.com
Jonas A. Nilsson, e-mail: firstname.lastname@example.org
Keywords: melanoma, miR210, hypoxia, xenografts, MEK inhibitor
Received: January 25, 2016 Accepted: March 04, 2016 Published: March 18, 2016
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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