Open AccessHedgehog‐EGFR cooperation response genes determine the oncogenic phenotype of basal cell carcinoma and tumour‐initiating pancreatic cancer cells
Author(s) -
Eberl Markus,
Klingler Stefan,
Mangelberger Doris,
Loipetzberger Andrea,
Damhofer Helene,
Zoidl Kerstin,
Schnidar Harald,
Hache Hendrik,
Bauer HansChristian,
Solca Flavio,
HauserKronberger Cornelia,
Ermilov Alexandre N.,
Verhaegen Monique E.,
Bichakjian Christopher K.,
Dlugosz Andrzej A.,
Nietfeld Wilfried,
Sibilia Maria,
Lehrach Hans,
Wierling Christoph,
Aberger Fritz
Publication year - 2012
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201100201
Subject(s) - hedgehog , cancer research , epidermal growth factor receptor , hedgehog signaling pathway , biology , egfr inhibitors , pancreatic cancer , smoothened , cancer , signal transduction , microbiology and biotechnology , genetics
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.