Abstract LB-73: SOX9 regulates EGFR/ERBB signaling in pancreatic cancer

Abstract

Abstract The transcription factor SOX9 has recently been shown to have a role in the ontogenesis of pancreatic ductal adenocarcinoma (PDAC) through metaplastic changes in pancreatic acinar cells. Nevertheless, the mechanisms through which SOX9 operates remain to be explored. We analyzed genomic and transcriptomic data from a cohort of surgically resected cases of PDAC (n=90) from the Australian Pancreatic cancer Genome Initiative (APGI). Genetic aberrations (mutation and copy number changes) in the SOX9 gene were found in 15% of patient tumors. Protein expression analysis revealed that most PDAC samples strongly express SOX9 protein and differential SOX9 expression correlates with patient survival. SOX9 gene expression was higher in the classical PDAC subtype, which relates with better patient outcome and increased response to epidermal growth factor receptor (EGFR)-directed therapy. In patient tumors, we found that SOX9 expression correlates with expression of EGFR signaling pathway genes, including ErbB2. Analysis of patient-derived xenografts confirmed strong correlation of SOX9 and ErbB2 expression and manipulation of human tumor cell lines demonstrated that Sox9 regulates the expression of ErbB2. We extended these findings by using a mouse model lacking pancreatic Sox9 expression where we found reduced expression of Egfr/ErbB signaling components. Sox9-deficient pancreatic acinar cells failed to generate PDAC precursor lesions and did not respond to EGF, indicating that Sox9 is required for Egfr/ErbB signaling pathway activity. In conclusion, by using an integrative approach that combines human and mouse models data, we discovered a new function of SOX9 in the regulation of EGFR/ERBB signaling throughout pancreatic tumorigenesis. This provides a novel mechanistic insight of potential therapeutic significance for pancreatic cancer patients. Citation Format: Andreia V. Pinho, Adrien Grimont, Mark J. Cowley, Cecile Augereau, Amanda Mawson, Marc Giry-Laterriere, Geraldine Van den Steen, Nicola Waddell, Marina Pajic, Christine Sempoux, Australian Pancreatic Cancer Genome Initiative, Jianmin Wu, Sean M. Grimmond, Andrew V. Biankin, Frederic P. Lemaigre, Patrick Jacquemin, Ilse Rooman. SOX9 regulates EGFR/ERBB signaling in pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-73. doi:10.1158/1538-7445.AM2014-LB-73