title: Activin upregulation by NF-κB is required to maintain mesenchymal features of cancer stem-like cells in non-small cell lung cancer.
abstract: Soluble growth factors and cytokines within the tumor microenvironment aid in the induction of the epithelial-to-mesenchymal transition (EMT). Although EMT promotes the development of cancer-initiating cells (CIC), cellular mechanisms by which cancer cells maintain mesenchymal phenotypes remain poorly understood. Work presented here indicates that induction of EMT stimulates non-small cell lung cancer (NSCLC) to secrete soluble factors that function in an autocrine fashion. Using gene expression profiling of all annotated and predicted secreted gene products, we find that NF-κB activity is required to upregulate INHBA/Activin, a morphogen in the TGFβ superfamily. INHBA is capable of inducing and maintaining mesenchymal phenotypes, including the expression of EMT master-switch regulators and self-renewal factors that sustain CIC phenotypes and promote lung metastasis. Our work demonstrates that INHBA mRNA and protein expression are commonly elevated in primary human NSCLC and provide evidence that INHBA is a critical autocrine factor that maintains mesenchymal properties of CICs to promote metastasis in NSCLC.
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia.
authors.forename: J Jacob
authors.initials: JJ
authors.lastname: Wamsley
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia.
authors.forename: Manish
authors.initials: M
authors.lastname: Kumar
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia.
authors.forename: David F
authors.initials: DF
authors.lastname: Allison
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia.
authors.forename: Sheena H
authors.initials: SH
authors.lastname: Clift
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia.
authors.forename: Caitlyn M
authors.initials: CM
authors.lastname: Holzknecht
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia.
authors.forename: Szymon J
authors.initials: SJ
authors.lastname: Szymura
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Hoang
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia.
authors.forename: Xiaojiang
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Pathology, University of Virginia, Charlottesville, Virginia.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Moskaluk
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia. Department of Thoracic Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: David R
authors.initials: DR
authors.lastname: Jones
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia.
authors.forename: Stefan
authors.initials: S
authors.lastname: Bekiranov
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia. mwm3y@virginia.edu sb3de@Virginia.edu.
authors.forename: Marty W
authors.initials: MW
authors.lastname: Mayo
mesh_terms: D028341:Activins / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D028322:Inhibin-beta Subunits / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D018874:Spheroids, Cellular; D015854:Up-Regulation
chemical_list: D016328:NF-kappa B; D012334:RNA, Neoplasm; C103008:inhibin beta A subunit; D028341:Activins; D028322:Inhibin-beta Subunits