Journal
CELL
Volume 166, Issue 2, Pages 328-342Publisher
CELL PRESS
DOI: 10.1016/j.cell.2016.05.052
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Funding
- Stanford Cancer Institute Cancer Biology Seed Grant
- Stanford Cancer Institute [NIH P30-CA124435]
- NIH [P50HG007735, R01CA206540, F32-CA189659]
- Baxter Foundation Faculty Scholar Grant
- Rita Allen Foundation
- Human Frontier Science Program
- Stanford Biophysics training grant [T32 GM008294]
- NSF GRFP
- Stanford Graduate Fellowship
- TRDRP Dissertation Award [24DT-0001]
- American Lung Association Fellowship
- Hope Funds for Cancer Research [HFCR-15-06-07]
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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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