Yang, Dian, Denny, Sarah K., Greenside, Peyton G., Chaikovsky, Andrea C., Brady, Jennifer J., Ouadah, Youcef, Granja, Jeffrey M., Jahchan, Nadine S., Lim, Jing Shan, Kwok, Shirley, Kong, Christina S., Berghoff, Anna S., Schmitt, Anna, Reinhardt, H. Christian, Park, Kwon-Sik, Preusser, Matthias, Kundaje, Anshul ORCID: 0000-0003-3084-2287, Greenleaf, William J., Sage, Julien and Winslow, Monte M. (2018). Intertumoral Heterogeneity in SCLC Is Influenced by the Cell Type of Origin. Cancer Discov., 8 (10). S. 1316 - 1332. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 2159-8290

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Abstract

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. (C) 2018 AACR.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Yang, DianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Denny, Sarah K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Greenside, Peyton G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chaikovsky, Andrea C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brady, Jennifer J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ouadah, YoucefUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Granja, Jeffrey M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jahchan, Nadine S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lim, Jing ShanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kwok, ShirleyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kong, Christina S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Berghoff, Anna S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmitt, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reinhardt, H. ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Park, Kwon-SikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Preusser, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kundaje, AnshulUNSPECIFIEDorcid.org/0000-0003-3084-2287UNSPECIFIED
Greenleaf, William J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sage, JulienUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Winslow, Monte M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-171454
DOI: 10.1158/2159-8290.CD-17-0987
Journal or Publication Title: Cancer Discov.
Volume: 8
Number: 10
Page Range: S. 1316 - 1332
Date: 2018
Publisher: AMER ASSOC CANCER RESEARCH
Place of Publication: PHILADELPHIA
ISSN: 2159-8290
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
PULMONARY NEUROENDOCRINE CELLS; LUNG-CANCER; LINEAGE PLASTICITY; INITIATING CELLS; MOUSE MODEL; CARCINOMA; PROGRESSION; EXPRESSION; CHROMATIN; TRP53Multiple languages
OncologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/17145

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