[HTML][HTML] Nfib promotes metastasis through a widespread increase in chromatin accessibility

SK Denny, D Yang, CH Chuang, JJ Brady, JS Lim… - Cell, 2016 - cell.com
SK Denny, D Yang, CH Chuang, JJ Brady, JS Lim, BM Grüner, SH Chiou, AN Schep, J Baral
Cell, 2016cell.com
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 …
Summary
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.
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