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

Eberl, M., Klingler, S., Mangelberger, D., Loipetzberger, A., Damhofer, H., Zoidl, K., Schnidar, H., Hache, H., Bauer, H. C., Solca, F., Hauser-Kronberger, C., Ermilov, A. N., Verhaegen, M. E., Bichakjian, C. K., Dlugosz, A. A., Nietfeld, W., Sibilia, M., Lehrach, H., Wierling, C., Aberger, F. (2012) Hedgehog-EGFR cooperation response genes determine the oncogenic phenotype of basal cell carcinoma and tumour-initiating pancreatic cancer cells. EMBO Molecular Medicine, 4 (3). pp. 218-233. ISSN 17574676 (ISSN)

URL: http://www.ncbi.nlm.nih.gov/pubmed/22294553
DOI: 10.1002/emmm.201100201

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. © 2012 EMBO Molecular Medicine.

Item Type: Paper
Subjects: diseases & disorders > cancer
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > epidermal growth factor
diseases & disorders > cancer > cancer types > pancreatic cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
CSHL Authors:
Communities: CSHL labs > Zheng lab
Depositing User: Matt Covey
Date: 2012
Date Deposited: 31 Jan 2013 17:56
Last Modified: 31 Jan 2013 17:56
PMCID: PMC3305999
Related URLs:
URI: http://repository.cshl.edu/id/eprint/26933

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