title: FOXF1 mediates mesenchymal stem cell fusion-induced reprogramming of lung cancer cells.
abstract: Several reports suggest that malignant cells generate phenotypic diversity through fusion with various types of stromal cells within the tumor microenvironment. Mesenchymal stem cell (MSC) is one of the critical components in the tumor microenvironment and a promising fusogenic candidate, but the underlying functions of MSC fusion with malignant cell have not been fully examined. Here, we demonstrate that MSCs fuse spontaneously with lung cancer cells, and the latter is reprogrammed to slow growth and stem-like state. Transcriptome profiles reveal that lung cancer cells are reprogrammed to a more benign state upon MSC fusion. We further identified FOXF1 as a reprogramming mediator that contributes not only to the reprogramming toward stemness but also to the p21-regulated growth suppression in fusion progeny. Collectively, MSC fusion does not enhance the intrinsic malignancy of lung cancer cells. The anti-malignant effects of MSC fusion-induced reprogramming on lung cancer cells were accomplished by complementation of tumorigenic defects, including restoration of p21 function and normal terminal differentiation pathways as well as up-regulation of FOXF1, a putative tumor suppressor. Such fusion process raises the therapeutic potential that MSC fusion can be utilized to reverse cellular phenotypes in cancer.
authors.affiliation: Graduate Institute of Biomedical Materials and Engineering, College of Oral Medicine, Taipei Medical University, Taipei 110, Taiwan. Stem Cell Research Center, Taipei Medical University, Taipei 110, Taiwan.
authors.forename: Hong-Jian
authors.initials: HJ
authors.lastname: Wei
authors.affiliation: Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, USA.
authors.forename: Jac A
authors.initials: JA
authors.lastname: Nickoloff
authors.affiliation: Stem Cell Research Center, Taipei Medical University, Taipei 110, Taiwan.
authors.forename: Wei-Hong
authors.initials: WH
authors.lastname: Chen
authors.affiliation: Stem Cell Research Center, Taipei Medical University, Taipei 110, Taiwan.
authors.forename: Hen-Yu
authors.initials: HY
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, Taipei Medical University Hospital, Taipei 110, Taiwan. School of Medicine, Taipei Medical University, Taipei 110, Taiwan.
authors.forename: Wen-Cheng
authors.initials: WC
authors.lastname: Lo
authors.affiliation: Graduate Institute of Biomedical Materials and Engineering, College of Oral Medicine, Taipei Medical University, Taipei 110, Taiwan.
authors.forename: Ya-Ting
authors.initials: YT
authors.lastname: Chang
authors.affiliation: Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Pan-Chyr
authors.initials: PC
authors.lastname: Yang
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang Ming University, Taipei 112, Taiwan.
authors.forename: Cheng-Wen
authors.initials: CW
authors.lastname: Wu
authors.affiliation: Wake Forest Institute of Regenerative Medicine, Winston-Salem, NC 27157, USA.
authors.forename: David F
authors.initials: DF
authors.lastname: Williams
authors.affiliation: Department of Biomedical Engineering, College of Engineering and School of Medicine, Wayne State University, Detroit, MI 48201, USA Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Juri G
authors.initials: JG
authors.lastname: Gelovani
authors.affiliation: Graduate Institute of Biomedical Materials and Engineering, College of Oral Medicine, Taipei Medical University, Taipei 110, Taiwan. Stem Cell Research Center, Taipei Medical University, Taipei 110, Taiwan.
authors.forename: Win-Ping
authors.initials: WP
authors.lastname: Deng
mesh_terms: D000818:Animals; D002459:Cell Fusion; D049109:Cell Proliferation; D054338:Cell Transdifferentiation / Q000235:genetics*; D065150:Cellular Reprogramming; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology*; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D016513:Mice, SCID; D034622:RNA Interference; D034741:RNA, Small Interfering; D018874:Spheroids, Cellular; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; C098521:FOXF1 protein, human; D051858:Forkhead Transcription Factors; D034741:RNA, Small Interfering