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

• Published in: EMBO molecular medicine Vol. 4; no. 3; pp. 218 - 233
• Main Authors: Eberl, Markus, Klingler, Stefan, Mangelberger, Doris, Loipetzberger, Andrea, Damhofer, Helene, Zoidl, Kerstin, Schnidar, Harald, Hache, Hendrik, Bauer, Hans‐Christian, Solca, Flavio, Hauser‐Kronberger, Cornelia, Ermilov, Alexandre N., Verhaegen, Monique E., Bichakjian, Christopher K., Dlugosz, Andrzej A., Nietfeld, Wilfried, Sibilia, Maria, Lehrach, Hans, Wierling, Christoph, Aberger, Fritz
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2012; WILEY‐VCH Verlag; EMBO Press; WILEY-VCH Verlag
• Subjects: Animal models; Animals; Basal cell carcinoma; Binding sites; cancer; Carcinoma, Basal Cell - genetics; Carcinoma, Basal Cell - metabolism; Carcinoma, Basal Cell - pathology; Cell Line, Tumor; Cell proliferation; Cooperation; Cooperativity; CXCR4 protein; Drug resistance; Epidermal growth factor; epidermal growth factor receptor; Epidermal growth factor receptors; Fibroblast Growth Factors - genetics; Fibroblast Growth Factors - metabolism; Gene expression; Gene Expression Regulation, Neoplastic; Genetic transformation; Hedgehog protein; Hedgehog Proteins - genetics; Hedgehog Proteins - metabolism; Hedgehog signalling; Humans; Integration; Melanoma; Metastasis; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutagenesis; Pancreatic cancer; Pancreatic carcinoma; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Phenotype; Phenotypes; Receptor, Epidermal Growth Factor - genetics; Receptor, Epidermal Growth Factor - metabolism; Receptors, CXCR4 - genetics; Receptors, CXCR4 - metabolism; Research Article; Signal transduction; Skin cancer; Sox9 protein; SOX9 Transcription Factor - genetics; SOX9 Transcription Factor - metabolism; SOXB1 Transcription Factors - genetics; SOXB1 Transcription Factors - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor Burden; Tumors; Zinc Finger Protein GLI1; cancer; Hedgehog signalling; signal transduction; epidermal growth factor receptor
• ISSN: 1757-4676; 1757-4684
• DOI: 10.1002/emmm.201100201

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.