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

EMBO Molecular Medicine

Markus Eberl³  Stefan Klingler³  Doris Mangelberger³  Andrea Loipetzberger³  Helene Damhofer³  Kerstin Zoidl³  Harald Schnidar³  Hendrik Hache⁷  Hans-Christian Bauer⁴  Flavio Solca⁸  Cornelia Hauser-Kronberger¹  Alexandre N. Ermilov⁵  Monique E. Verhaegen⁵  Christopher K. Bichakjian⁵  Andrzej A. Dlugosz²  Wilfried Nietfeld⁷  Maria Sibilia⁶  Hans Lehrach⁷  Christoph Wierling⁷ 

[1] Department of Pathology, Paracelsus Medical University Salzburg, Salzburg, Austria;Departments of Dermatology and Cell & Developmental Biology, University of Michigan, MI, USA;Department of Molecular Biology, University of Salzburg, Salzburg, Austria;Department of Organismic Biology, University of Salzburg, Salzburg, Austria;Department of Dermatology, University of Michigan, MI, USA;Institute of Cancer Research, Medical University of Vienna, Vienna, Austria;Department of Vertebrate Genomics, Max-Planck Institute for Molecular Genetics, Berlin, Germany;Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria

关键词: cancer;    epidermal growth factor receptor;    Hedgehog signalling;    signal transduction;   

DOI  :  10.1002/emmm.201100201

来源: Wiley

【 摘 要 】

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.

【 授权许可】

Unknown   
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