title: Epithelial NF-κB signaling promotes EGFR-driven lung carcinogenesis via macrophage recruitment.
abstract: Several studies have demonstrated that NF-κB activation is common in lung cancer; however, the mechanistic links between NF-κB signaling and tumorigenesis remain to be fully elucidated. We investigated the function of NF-κB signaling in epidermal growth factor receptor (EGFR)-mutant lung tumors using a transgenic mouse model with doxycycline (dox)-inducible expression of oncogenic EGFR in the lung epithelium with or without a dominant inhibitor of NF-κB signaling. NF-κB inhibition resulted in a significant reduction in tumor burden in both EGFR tyrosine kinase inhibitor (TKI)-sensitive and resistant tumors. However, NF-κB inhibition did not alter epithelial cell survival in vitro or in vivo, and no changes were detected in activation of EGFR downstream signaling pathways. Instead, we observed an influx of inflammatory cells (macrophages and neutrophils) in the lungs of mice with oncogenic EGFR expression that was blocked in the setting of NF-κB inhibition. To investigate whether inflammatory cells play a role in promoting EGFR-mutant lung tumors, we depleted macrophages and neutrophils during tumorigenesis and found that neutrophil depletion had no effect on tumor formation, but macrophage depletion caused a significant reduction in tumor burden. Together, these data suggest that epithelial NF-κB signaling supports carcinogenesis in a non-cell autonomous manner in EGFR-mutant tumors through recruitment of pro-tumorigenic macrophages.
authors.affiliation: Department of Cancer Biology, Vanderbilt University , Nashville, TN, USA.
authors.forename: Jamie A
authors.initials: JA
authors.lastname: Saxon
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center , Nashville, TN, USA.
authors.forename: Taylor P
authors.initials: TP
authors.lastname: Sherrill
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center , Nashville, TN, USA.
authors.forename: Vasiliy V
authors.initials: VV
authors.lastname: Polosukhin
authors.affiliation: Department of Cancer Biology, Vanderbilt University , Nashville, TN, USA.
authors.forename: Jiqing
authors.initials: J
authors.lastname: Sai
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center , Nashville, TN, USA.
authors.forename: Rinat
authors.initials: R
authors.lastname: Zaynagetdinov
authors.affiliation: Department of Cancer Biology, Vanderbilt University , Nashville, TN, USA.
authors.forename: Allyson G
authors.initials: AG
authors.lastname: McLoed
authors.affiliation: Department of Pediatrics, Division of Pulmonary Medicine, Vanderbilt University Medical Center , Nashville, TN, USA.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Gulleman
authors.affiliation: Department of Cancer Biology, Vanderbilt University , Nashville, TN, USA.
authors.forename: Whitney
authors.initials: W
authors.lastname: Barham
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center , Nashville, TN, USA.
authors.forename: Dong-Sheng
authors.initials: DS
authors.lastname: Cheng
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center , Nashville, TN, USA.
authors.forename: Raphael P
authors.initials: RP
authors.lastname: Hunt
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center , Nashville, TN, USA.
authors.forename: Linda A
authors.initials: LA
authors.lastname: Gleaves
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, TN, USA; Department of Veterans Affairs Medical Center, Nashville, TN, USA.
authors.forename: Ann
authors.initials: A
authors.lastname: Richmond
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Pediatrics, Division of Pulmonary Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA.
authors.forename: Lisa R
authors.initials: LR
authors.lastname: Young
authors.affiliation: Department of Cancer Biology, Vanderbilt University , Nashville, TN, USA.
authors.forename: Fiona E
authors.initials: FE
authors.lastname: Yull
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, TN, USA; Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Veterans Affairs Medical Center, Nashville, TN, USA; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Blackwell
keywords: EGFR; NF-κB; lung cancer; macrophage; neutrophil