Intertumoral Heterogeneity in SCLC Is Influenced by the Cell Type of Origin.

Autor:	Yang D; Cancer Biology Program, Stanford University, Stanford, California.; Department of Genetics, Stanford University, Stanford, California.; Department of Pediatrics, Stanford University, Stanford, California., Denny SK; Department of Genetics, Stanford University, Stanford, California.; Biophysics Program, Stanford University, Stanford, California., Greenside PG; Program in Biomedical Informatics, Stanford University, Stanford, California., Chaikovsky AC; Cancer Biology Program, Stanford University, Stanford, California.; Department of Genetics, Stanford University, Stanford, California.; Department of Pediatrics, Stanford University, Stanford, California., Brady JJ; Department of Genetics, Stanford University, Stanford, California., Ouadah Y; Cancer Biology Program, Stanford University, Stanford, California.; Department of Biochemistry, Stanford University, Stanford, California., Granja JM; Department of Genetics, Stanford University, Stanford, California.; Biophysics Program, Stanford University, Stanford, California., Jahchan NS; Department of Genetics, Stanford University, Stanford, California.; Department of Pediatrics, Stanford University, Stanford, California., Lim JS; Cancer Biology Program, Stanford University, Stanford, California.; Department of Genetics, Stanford University, Stanford, California.; Department of Pediatrics, Stanford University, Stanford, California., Kwok S; Department of Pathology, Stanford University, Stanford, California., Kong CS; Department of Pathology, Stanford University, Stanford, California., Berghoff AS; Institute of Neurology, Medical University of Vienna, Vienna, Austria.; Department of Medicine I, Medical University of Vienna, Vienna, Austria.; Comprehensive Cancer Center CNS Tumors Unit, Medical University of Vienna, Vienna, Austria., Schmitt A; Department of Internal Medicine I, University Hospital of Cologne, Cologne, Germany., Reinhardt HC; Department of Internal Medicine I, University Hospital of Cologne, Cologne, Germany.; Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Cologne, Germany.; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany., Park KS; Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia., Preusser M; Department of Medicine I, Medical University of Vienna, Vienna, Austria.; Comprehensive Cancer Center CNS Tumors Unit, Medical University of Vienna, Vienna, Austria., Kundaje A; Department of Genetics, Stanford University, Stanford, California.; Department of Computer Science, Stanford University, Stanford, California., Greenleaf WJ; Department of Genetics, Stanford University, Stanford, California., Sage J; Cancer Biology Program, Stanford University, Stanford, California. mwinslow@stanford.edu julsage@stanford.edu.; Department of Genetics, Stanford University, Stanford, California.; Department of Pediatrics, Stanford University, Stanford, California., Winslow MM; Cancer Biology Program, Stanford University, Stanford, California. mwinslow@stanford.edu julsage@stanford.edu.; Department of Genetics, Stanford University, Stanford, California.; Department of Pathology, Stanford University, Stanford, California.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2018 Oct; Vol. 8 (10), pp. 1316-1331. Date of Electronic Publication: 2018 Sep 18.
DOI:	10.1158/2159-8290.CD-17-0987
Abstrakt:	The extent to which early events shape tumor evolution is largely uncharacterized, even though a better understanding of these early events may help identify key vulnerabilities in advanced tumors. Here, using genetically defined mouse models of small cell lung cancer (SCLC), we uncovered distinct metastatic programs attributable to the cell type of origin. In one model, tumors gain metastatic ability through amplification of the transcription factor NFIB and a widespread increase in chromatin accessibility, whereas in the other model, tumors become metastatic in the absence of NFIB-driven chromatin alterations. Gene-expression and chromatin accessibility analyses identify distinct mechanisms as well as markers predictive of metastatic progression in both groups. Underlying the difference between the two programs was the cell type of origin of the tumors, with NFIB-independent metastases arising from mature neuroendocrine cells. Our findings underscore the importance of the identity of cell type of origin in influencing tumor evolution and metastatic mechanisms. Significance: We show that SCLC can arise from different cell types of origin, which profoundly influences the eventual genetic and epigenetic changes that enable metastatic progression. Understanding intertumoral heterogeneity in SCLC, and across cancer types, may illuminate mechanisms of tumor progression and uncover how the cell type of origin affects tumor evolution. Cancer Discov; 8(10); 1316-31. ©2018 AACR. See related commentary by Pozo et al., p. 1216 This article is highlighted in the In This Issue feature, p. 1195 . (©2018 American Association for Cancer Research.)
Databáze:	MEDLINE
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