A novel NHE1-centered signaling cassette drives EGFR-dependent pancreatic tumor metastasis and is a target for combination therapy

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers principally due to early invasion and metastasis. The 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 data base 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 3D growth and early invasion via invadopodial ECM digestion. EGF promoted the complexing of EGFR with NHE1 via the scaffolding protein NHERF1, engaging EGFR in a negative trans-regulatory 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/NHERF1/NHE1 signaling complex into dimeric subcomplexes in different lipid raft-like membrane domains. This signaling complex was also found in tumors developed in orthotopic mice. Importantly, the specific NHE1 inhibitor, Cariporide, reduced both 3D growth and invasion independently of PDAC subtype and synergistically sensitized these behaviors to low doses of erlotinib.