FGFR2 signaling underlies p63 oncogenic function in squamous cell carcinoma

Ramsey, M. R., Wilson, C., Ory, B., Rothenberg, S. M., Faquin, W., Mills, A. A., Ellisen, L. W. (August 2013) FGFR2 signaling underlies p63 oncogenic function in squamous cell carcinoma. Journal of Clinical Investigation, 123 (8). pp. 3525-3538. ISSN 0021-9738

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URL: http://www.ncbi.nlm.nih.gov/pubmed/23867503
DOI: 10.1172/Jci68899

Abstract

Oncogenic transcription factors drive many human cancers, yet identifying and therapeutically targeting the resulting deregulated pathways has proven difficult. Squamous cell carcinoma (SCC) is a common and lethal human cancer, and relatively little progress has been made in improving outcomes for SCC due to a poor understanding of its underlying molecular pathogenesis. While SCCs typically lack somatic oncogene-activating mutations, they exhibit frequent overexpression of the p53-related transcription factor p63. We developed an in vivo murine tumor model to investigate the function and key transcriptional programs of p63 in SCC. Here, we show that established SCCs are exquisitely dependent on p63, as acute genetic ablation of p63 in advanced, invasive SCC induced rapid and dramatic apoptosis and tumor regression. In vivo genome-wide gene expression analysis identified a tumor-survival program involving p63-regulated FGFR2 signaling that was activated by ligand emanating from abundant tumor-associated stroma. Correspondingly, we demonstrate the therapeutic efficacy of extinguishing this signaling axis in endogenous SCCs using the clinical FGFR2 inhibitor AZD4547. Collectively, these results reveal an unanticipated role for p63-driven paracrine FGFR2 signaling as an addicting pathway in human cancer and suggest a new approach for the treatment of SCC.

Item Type: Paper
Uncontrolled Keywords: tyrosine kinase inhibitor phase-ii trial growth-factor neck-cancer tumor progression metastatic head skin tumors mouse model expression mice
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > fibroblast growth factor
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > oncogene
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > p63
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein receptor
CSHL Authors:
Communities: CSHL Cancer Center Program > Cancer Genetics
CSHL Cancer Center Shared Resources > Animal Services
CSHL Cancer Center Shared Resources > Gene Targeting Service
CSHL labs > Mills lab
CSHL Cancer Center Shared Resources > Functional Genomics and Genetics Service
Depositing User: Matt Covey
Date: August 2013
Date Deposited: 26 Dec 2014 15:33
Last Modified: 30 Oct 2015 16:49
PMCID: PMC3726171
Related URLs:
URI: http://repository.cshl.edu/id/eprint/30989

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