title: Hypoxia-regulated gene expression explains differences between melanoma cell line-derived xenografts and patient-derived xenografts.
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.
authors.affiliation: Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Joydeep
authors.initials: J
authors.lastname: Bhadury
authors.affiliation: Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Berglind O
authors.initials: BO
authors.lastname: Einarsdottir
authors.affiliation: Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Podraza
authors.affiliation: Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Roger Olofsson
authors.initials: RO
authors.lastname: Bagge
authors.affiliation: Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Ulrika
authors.initials: U
authors.lastname: Stierner
authors.affiliation: Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Ny
authors.affiliation: The Bioinformatics Core Facility at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Marcela
authors.initials: M
authors.lastname: Dávila López
authors.affiliation: Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Jonas A
authors.initials: JA
authors.lastname: Nilsson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics*; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics*; D059467:Transcriptome; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C543800:MIRN210 microRNA, human; D035683:MicroRNAs
keywords: MEK inhibitor; hypoxia; melanoma; miR210; xenografts