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

Joydeep Bhadury*, Berglind O. Einarsdottir, Agnieszka Podraza, Roger Bagge Olofsson, Ulrika Stierner, Lars Ny, Marcela Dávila López, Jonas A. Nilsson

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

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 hypoxiaregulated 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.

Original languageEnglish
Pages (from-to)23801-23811
Number of pages11
JournalOncotarget
Volume7
Issue number17
DOIs
Publication statusPublished - 26 Apr 2016

Other keywords

  • Hypoxia
  • MEK inhibitor
  • Melanoma
  • miR210
  • Xenografts

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