Transcription Factor NFIB Is a Driver of Small Cell Lung Cancer Progression in Mice and Marks Metastatic Disease in Patients

Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor, and no effective treatment is available to date. Mouse models of SCLC based on the inactivation of Rb1 and Trp53 show frequent amplifications of the Nfib and Mycl genes. Here, we report that, although overexpression of either trans...

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Bibliographic Details
Published in:	Cell reports (Cambridge) Vol. 16; no. 3; pp. 631 - 643
Main Authors:	Semenova, Ekaterina A., Kwon, Min-chul, Monkhorst, Kim, Song, Ji-Ying, Bhaskaran, Rajith, Krijgsman, Oscar, Kuilman, Thomas, Peters, Dennis, Buikhuisen, Wieneke A., Smit, Egbert F., Pritchard, Colin, Cozijnsen, Miranda, van der Vliet, Jan, Zevenhoven, John, Lambooij, Jan-Paul, Proost, Natalie, van Montfort, Erwin, Velds, Arno, Huijbers, Ivo J., Berns, Anton
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 19.07.2016 Cell Press Elsevier
Subjects:	Animals Biomarkers, Tumor - metabolism Cadherins - metabolism Cell Proliferation - physiology Disease Models, Animal Disease Progression Gene Expression Regulation, Neoplastic - physiology Humans Lung Neoplasms - metabolism Lung Neoplasms - pathology Mice Neoplasm Metastasis - pathology NFI Transcription Factors - metabolism Proto-Oncogene Proteins c-myc - metabolism Retinoblastoma Protein - metabolism Small Cell Lung Carcinoma - metabolism Small Cell Lung Carcinoma - pathology Tumor Suppressor Protein p53 - metabolism
ISSN:	2211-1247, 2211-1247
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Summary:	Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor, and no effective treatment is available to date. Mouse models of SCLC based on the inactivation of Rb1 and Trp53 show frequent amplifications of the Nfib and Mycl genes. Here, we report that, although overexpression of either transcription factor accelerates tumor growth, NFIB specifically promotes metastatic spread. High NFIB levels are associated with expansive growth of a poorly differentiated and almost exclusively E-cadherin (CDH1)-negative invasive tumor cell population. Consistent with the mouse data, we find that NFIB is overexpressed in almost all tested human metastatic high-grade neuroendocrine lung tumors, warranting further assessment of NFIB as a tumor progression marker in a clinical setting. [Display omitted] •NFIB drives tumor initiation and progression in mouse models of SCLC•NFIB enhances metastasis and changes the metastatic profile•NFIB promotes dedifferentiation and invasion in SCLC•NFIB marks stage III/IV high-grade neuroendocrine carcinomas in patients SCLC is a highly malignant cancer with an unmet need for better intervention strategies. Semenova et al. report that the transcription factor NFIB drives SCLC growth and metastasis, defines an aggressive tumor compartment in mice, and marks a subgroup of high-grade pulmonary neuroendocrine tumors (pNETs) in patients.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Co-senior author Co-first author
ISSN:	2211-1247 2211-1247
DOI:	10.1016/j.celrep.2016.06.020