Simultaneous evaluation of anti-EGFR-induced tumour and adverse skin effects in a microfluidic human 3D co-culture model

Research output: Contribution to journalArticle

  • External authors:
  • Juliane Hübner
  • Marian Raschke
  • Isabel Rütschle
  • Sarah Gräßle
  • Tobias Hasenberg
  • Alexandra Lorenz
  • Susanne Schnurre
  • Roland Lauster
  • Ilka Maschmeyer
  • Thomas Steger-Hartmann
  • Uwe Marx

Abstract

Antibody therapies targeting the epithelial growth factor receptor (EGFR) are being increasingly applied in cancer therapy. However, increased tumour containment correlates proportionally with the severity of well-known adverse events in skin. The prediction of the latter is not currently possible in conventional in vitro systems and limited in existing laboratory animal models. Here we established a repeated dose "safficacy" test assay for the simultaneous generation of safety and efficacy data. Therefore, a commercially available multi-organ chip platform connecting two organ culture compartments was adapted for the microfluidic co-culture of human H292 lung cancer microtissues and human full-thickness skin equivalents. Repeated dose treatment of the anti-EGFR-antibody cetuximab showed an increased pro-apoptotic related gene expression in the tumour microtissues. Simultaneously, proliferative keratinocytes in the basal layer of the skin microtissues were eliminated, demonstrating crucial inhibitory effects on the physiological skin cell turnover. Furthermore, antibody exposure modulated the release of CXCL8 and CXCL10, reflecting the pattern changes seen in antibody-treated patients. The combination of a metastatic tumour environment with a miniaturized healthy organotypic human skin equivalent make this "safficacy" assay an ideal tool for evaluation of the therapeutic index of EGFR inhibitors and other promising oncology candidates.

Bibliographical metadata

Original languageEnglish
Pages (from-to)15010
JournalScientific Reports
Volume8
Issue number1
Early online date9 Oct 2018
DOIs
Publication statusPublished - 2018