title: Nfib Promotes Metastasis through a Widespread Increase in Chromatin Accessibility.
abstract: Metastases are the main cause of cancer deaths, but the mechanisms underlying metastatic progression remain poorly understood. We isolated pure populations of cancer cells from primary tumors and metastases from a genetically engineered mouse model of human small cell lung cancer (SCLC) to investigate the mechanisms that drive the metastatic spread of this lethal cancer. Genome-wide characterization of chromatin accessibility revealed the opening of large numbers of distal regulatory elements across the genome during metastatic progression. These changes correlate with copy number amplification of the Nfib locus, and differentially accessible sites were highly enriched for Nfib transcription factor binding sites. Nfib is necessary and sufficient to increase chromatin accessibility at a large subset of the intergenic regions. Nfib promotes pro-metastatic neuronal gene expression programs and drives the metastatic ability of SCLC cells. The identification of widespread chromatin changes during SCLC progression reveals an unexpected global reprogramming during metastatic progression.
authors.affiliation: Biophysics Program, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Denny
authors.affiliation: Cancer Biology Program, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Dian
authors.initials: D
authors.lastname: Yang
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Chen-Hua
authors.initials: CH
authors.lastname: Chuang
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Brady
authors.affiliation: Cancer Biology Program, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Jing Shan
authors.initials: JS
authors.lastname: Lim
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Grüner
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Shin-Heng
authors.initials: SH
authors.lastname: Chiou
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Alicia N
authors.initials: AN
authors.lastname: Schep
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Jessika
authors.initials: J
authors.lastname: Baral
authors.affiliation: Service de Pneumologie, Hôpital Tenon-APHP, Université Paris 6 Pierre et Marie Curie, 75020 Paris, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Hamard
authors.affiliation: Service de Pneumologie, Hôpital Tenon-APHP, Université Paris 6 Pierre et Marie Curie, 75020 Paris, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Antoine
authors.affiliation: Service de Pneumologie, Hôpital Tenon-APHP, Université Paris 6 Pierre et Marie Curie, 75020 Paris, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Wislez
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Christina S
authors.initials: CS
authors.lastname: Kong
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Connolly
authors.affiliation: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
authors.forename: Kwon-Sik
authors.initials: KS
authors.lastname: Park
authors.affiliation: Cancer Biology Program, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Julien
authors.initials: J
authors.lastname: Sage
authors.affiliation: Biophysics Program, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Applied Physics, Stanford University, Stanford, CA 94305, USA. Electronic address: wjg@stanford.edu.
authors.forename: William J
authors.initials: WJ
authors.lastname: Greenleaf
authors.affiliation: Cancer Biology Program, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: mwinslow@stanford.edu.
authors.forename: Monte M
authors.initials: MM
authors.lastname: Winslow
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D051839:NFI Transcription Factors / Q000235:genetics / Q000378:metabolism*; D009362:Neoplasm Metastasis / Q000473:pathology*; D011401:Promoter Regions, Genetic; D055752:Small Cell Lung Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015854:Up-Regulation
chemical_list: D051839:NFI Transcription Factors; C484683:Nfib protein, mouse