A Novel NHE1-Centered Signaling Cassette Drives Epidermal Growth Factor Receptor–Dependent Pancreatic Tumor Metastasis and Is a Target for Combination Therapy

• Published in: Neoplasia (New York, N.Y.) Vol. 17; no. 2; pp. 155 - 166
• Main Authors: Cardone, Rosa Angela, Greco, Maria Raffaella, Zeeberg, Katrine, Zaccagnino, Angela, Saccomano, Mara, Bellizzi, Antonia, Bruns, Philipp, Menga, Marta, Pilarsky, Christian, Schwab, Albrecht, Alves, Frauke, Kalthoff, Holger, Casavola, Valeria, Reshkin, Stephan Joel
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2015; Elsevier
• Subjects: Animals; Anti-Arrhythmia Agents - therapeutic use; Blotting, Western; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - secondary; Cation Transport Proteins - metabolism; Cell Line; Cell Line, Tumor; Drug Therapy, Combination; Erlotinib Hydrochloride; Guanidines - therapeutic use; Humans; Mice; Mice, Nude; Mice, SCID; Oncology; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Protein Kinase Inhibitors - therapeutic use; Quinazolines - therapeutic use; Receptor, Epidermal Growth Factor - metabolism; Signal Transduction; Sodium-Hydrogen Exchanger 1; Sodium-Hydrogen Exchangers - metabolism; Sulfones - therapeutic use; Na +/H + exchanger isoform 1; NHE1; NHERF1; PDAC; epidermal growth factor receptor; Na +/H + exchanger regulatory factor 1; pancreatic ductual adenocarcinoma; EGFR
• ISSN: 1476-5586; 1522-8002; 1476-5586; 1522-8002
• DOI: 10.1016/j.neo.2014.12.003

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers principally because of early invasion and metastasis. The epidermal growth factor receptor (EGFR) is essential for PDAC development even in the presence of Kras, but its inhibition with erlotinib gives only a modest clinical response, making the discovery of novel EGFR targets of critical interest. Here, we revealed by mining a human pancreatic gene expression database that the metastasis promoter Na+ /H+ exchanger (NHE1) associates with the EGFR in PDAC. In human PDAC cell lines, we confirmed that NHE1 drives both basal and EGF-stimulated three-dimensional growth and early invasion via invadopodial extracellular matrix digestion. EGF promoted the complexing of EGFR with NHE1 via the scaffolding protein Na +/H + exchanger regulatory factor 1, engaging EGFR in a negative transregulatory loop that controls the extent and duration of EGFR oncogenic signaling and stimulates NHE1. The specificity of NHE1 for growth or invasion depends on the segregation of the transient EGFR/Na +/H + exchanger regulatory factor 1/NHE1 signaling complex into dimeric subcomplexes in different lipid raftlike membrane domains. This signaling complex was also found in tumors developed in orthotopic mice. Importantly, the specific NHE1 inhibitor cariporide reduced both three-dimensional growth and invasion independently of PDAC subtype and synergistically sensitized these behaviors to low doses of erlotinib.