A novel NHE1-centered signaling cassette drives epidermal growth factor receptor-dependent pancreatic tumor metastasis and is a target for combination therapy.
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.
Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Via E. Orabona 4, 70125, Bari, Italy.
Rosa Angela
RA
Cardone
Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Via E. Orabona 4, 70125, Bari, Italy.
Maria Raffaella
MR
Greco
Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Via E. Orabona 4, 70125, Bari, Italy.
Katrine
K
Zeeberg
Institute for Experimental Cancer Research, Christian Albrechts University, Arnold-Heller-Str. 7, D-24105, Kiel, Germany.
Angela
A
Zaccagnino
Max-Planck-Institute of Experimental Medicine, Hermann-Rein-Str. 3, D-37075, Gottingen, Germany.
Mara
M
Saccomano
Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Via E. Orabona 4, 70125, Bari, Italy.
Antonia
A
Bellizzi
Institute of Physiology II, University of Muenster, Robert-Koch-Str. 27 b, D-48149, Muenster, Germany.
Philipp
P
Bruns
Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Via E. Orabona 4, 70125, Bari, Italy.
Marta
M
Menga
University Hospital Carl Gustav Carus, Technical University of Dresden, TU Dresden, Fetscherstraße 74, D-01307, Dresden, Germany.
Christian
C
Pilarsky
Institute of Physiology II, University of Muenster, Robert-Koch-Str. 27 b, D-48149, Muenster, Germany.
Albrecht
A
Schwab
Max-Planck-Institute of Experimental Medicine, Hermann-Rein-Str. 3, D-37075, Gottingen, Germany.
Frauke
F
Alves
Institute for Experimental Cancer Research, Christian Albrechts University, Arnold-Heller-Str. 7, D-24105, Kiel, Germany.
Holger
H
Kalthoff
Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Via E. Orabona 4, 70125, Bari, Italy; Centre of Excellence in Comparative Genomics (CEGBA), Bari, Italy.
Valeria
V
Casavola
Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Via E. Orabona 4, 70125, Bari, Italy; Centre of Excellence in Comparative Genomics (CEGBA), Bari, Italy. Electronic address: stephanjoel.reshkin@uniba.it.
Stephan Joel
SJ
Reshkin
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use; D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary*; D027682:Cation Transport Proteins / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D004359:Drug Therapy, Combination; D066246:ErbB Receptors / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D006146:Guanidines / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011799:Quinazolines / Q000627:therapeutic use; D015398:Signal Transduction; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*; D013450:Sulfones / Q000627:therapeutic use
D000889:Anti-Arrhythmia Agents; D027682:Cation Transport Proteins; D006146:Guanidines; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C490998:SLC9A1 protein, human; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C093373:cariporide; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors