Advertisement

Open Access

Transparent Process

Hedgehog‐EGFR cooperation response genes determine the oncogenic phenotype of basal cell carcinoma and tumour‐initiating pancreatic cancer cells

Markus Eberl, Stefan Klingler, Doris Mangelberger, Andrea Loipetzberger, Helene Damhofer, Kerstin Zoidl, Harald Schnidar, Hendrik Hache, Hans‐Christian Bauer, Flavio Solca, Cornelia Hauser‐Kronberger, Alexandre N. Ermilov, Monique E. Verhaegen, Christopher K. Bichakjian, Andrzej A. Dlugosz, Wilfried Nietfeld, Maria Sibilia, Hans Lehrach, Christoph Wierling, Fritz Aberger

Author Affiliations

  1. Markus Eberl1,
  2. Stefan Klingler1,9,
  3. Doris Mangelberger1,
  4. Andrea Loipetzberger1,
  5. Helene Damhofer1,
  6. Kerstin Zoidl1,
  7. Harald Schnidar1,
  8. Hendrik Hache2,
  9. Hans‐Christian Bauer3,
  10. Flavio Solca4,
  11. Cornelia Hauser‐Kronberger5,
  12. Alexandre N. Ermilov6,
  13. Monique E. Verhaegen6,
  14. Christopher K. Bichakjian6,
  15. Andrzej A. Dlugosz7,
  16. Wilfried Nietfeld2,
  17. Maria Sibilia8,
  18. Hans Lehrach2,
  19. Christoph Wierling2 and
  20. Fritz Aberger (fritz.aberger{at}sbg.ac.at) *,1
  1. 1Department of Molecular Biology, University of Salzburg, Salzburg, Austria
  2. 2Department of Vertebrate Genomics, Max‐Planck Institute for Molecular Genetics, Berlin, Germany
  3. 3Department of Organismic Biology, University of Salzburg, Salzburg, Austria
  4. 4Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
  5. 5Department of Pathology, Paracelsus Medical University Salzburg, Salzburg, Austria
  6. 6Department of Dermatology, University of Michigan, MI, USA
  7. 7Departments of Dermatology and Cell & Developmental Biology, University of Michigan, MI, USA
  8. 8Institute of Cancer Research, Medical University of Vienna, Vienna, Austria
  9. 9Cold Spring Harbor Laboratory, New York, NY, USA
  1. *Tel: +43 662 8044 5792; Fax: +43 662 8044 183
View Full Text

Abstract

Inhibition of Hedgehog (HH)/GLI signalling in cancer is a promising therapeutic approach. Interactions between HH/GLI and other oncogenic pathways affect the strength and tumourigenicity of HH/GLI. Cooperation of HH/GLI with epidermal growth factor receptor (EGFR) signalling promotes transformation and cancer cell proliferation in vitro. However, the in vivo relevance of HH‐EGFR signal integration and the critical downstream mediators are largely undefined. In this report we show that genetic and pharmacologic inhibition of EGFR signalling reduces tumour growth in mouse models of HH/GLI driven basal cell carcinoma (BCC). We describe HH‐EGFR cooperation response genes including SOX2, SOX9, JUN, CXCR4 and FGF19 that are synergistically activated by HH‐EGFR signal integration and required for in vivo growth of BCC cells and tumour‐initiating pancreatic cancer cells. The data validate EGFR signalling as drug target in HH/GLI driven cancers and shed light on the molecular processes controlled by HH‐EGFR signal cooperation, providing new therapeutic strategies based on combined targeting of HH‐EGFR signalling and selected downstream target genes.

  • Received May 17, 2011.
  • Revision received December 9, 2011.
  • Accepted December 12, 2011.

View Full Text