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Cell. 2016 Jul 14;166(2):328-342. doi: 10.1016/j.cell.2016.05.052. Epub 2016 Jun 30.

Nfib Promotes Metastasis through a Widespread Increase in Chromatin Accessibility.

Author information

1
Biophysics Program, Stanford University School of Medicine, Stanford, CA 94305, USA.
2
Cancer Biology Program, Stanford University School of Medicine, Stanford, CA 94305, USA.
3
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
4
Service de Pneumologie, Hôpital Tenon-APHP, Université Paris 6 Pierre et Marie Curie, 75020 Paris, France.
5
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
6
Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
7
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.
8
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.
9
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.

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.

PMID:
27374332
PMCID:
PMC5004630
DOI:
10.1016/j.cell.2016.05.052
[Indexed for MEDLINE]
Free PMC Article

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