title: Hedgehog-EGFR cooperation response genes determine the oncogenic phenotype of basal cell carcinoma and tumour-initiating pancreatic cancer cells.
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.
authors.affiliation: Department of Molecular Biology, University of Salzburg, Salzburg, Austria.
authors.forename: Markus
authors.initials: M
authors.lastname: Eberl
authors.forename: Stefan
authors.initials: S
authors.lastname: Klingler
authors.forename: Doris
authors.initials: D
authors.lastname: Mangelberger
authors.forename: Andrea
authors.initials: A
authors.lastname: Loipetzberger
authors.forename: Helene
authors.initials: H
authors.lastname: Damhofer
authors.forename: Kerstin
authors.initials: K
authors.lastname: Zoidl
authors.forename: Harald
authors.initials: H
authors.lastname: Schnidar
authors.forename: Hendrik
authors.initials: H
authors.lastname: Hache
authors.forename: Hans-Christian
authors.initials: HC
authors.lastname: Bauer
authors.forename: Flavio
authors.initials: F
authors.lastname: Solca
authors.forename: Cornelia
authors.initials: C
authors.lastname: Hauser-Kronberger
authors.forename: Alexandre N
authors.initials: AN
authors.lastname: Ermilov
authors.forename: Monique E
authors.initials: ME
authors.lastname: Verhaegen
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Bichakjian
authors.forename: Andrzej A
authors.initials: AA
authors.lastname: Dlugosz
authors.forename: Wilfried
authors.initials: W
authors.lastname: Nietfeld
authors.forename: Maria
authors.initials: M
authors.lastname: Sibilia
authors.forename: Hans
authors.initials: H
authors.lastname: Lehrach
authors.forename: Christoph
authors.initials: C
authors.lastname: Wierling
authors.forename: Fritz
authors.initials: F
authors.lastname: Aberger
mesh_terms: D000818:Animals; D002280:Basal Cell Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden; D000071676:Zinc Finger Protein GLI1
chemical_list: C527276:CXCR4 protein, human; C117476:FGF19 protein, human; C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D019718:Receptors, CXCR4; C527782:SOX2 protein, human; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D055748:SOXB1 Transcription Factors; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D005346:Fibroblast Growth Factors; D066246:ErbB Receptors