ausblenden:
Schlagwörter:
Animals
Carcinoma, Basal Cell/genetics/*metabolism/pathology
Cell Line, Tumor
Fibroblast Growth Factors/genetics/metabolism
*Gene Expression Regulation, Neoplastic
Hedgehog Proteins/genetics/*metabolism
Humans
Mice
Mice, Inbred C57BL
Mice, Transgenic
Pancreatic Neoplasms/genetics/*metabolism/pathology
Phenotype
Receptor, Epidermal Growth Factor/genetics/*metabolism
Receptors, CXCR4/genetics/metabolism
SOX9 Transcription Factor/genetics/metabolism
SOXB1 Transcription Factors/genetics/metabolism
Transcription Factors/genetics/metabolism
Tumor Burden
Zusammenfassung:
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.
