title: Transcription Factor NFIB Is a Driver of Small Cell Lung Cancer Progression in Mice and Marks Metastatic Disease in Patients.
abstract: 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.
authors.affiliation: Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands.
authors.forename: Ekaterina A
authors.initials: EA
authors.lastname: Semenova
authors.affiliation: Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands.
authors.forename: Min-Chul
authors.initials: MC
authors.lastname: Kwon
authors.affiliation: Division of Pathology, The Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands.
authors.forename: Kim
authors.initials: K
authors.lastname: Monkhorst
authors.affiliation: Division of Experimental Animal Pathology, The Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands.
authors.forename: Ji-Ying
authors.initials: JY
authors.lastname: Song
authors.affiliation: Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands; Genomics Core Facility, The Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands.
authors.forename: Rajith
authors.initials: R
authors.lastname: Bhaskaran
authors.affiliation: Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands.
authors.forename: Oscar
authors.initials: O
authors.lastname: Krijgsman
authors.affiliation: Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kuilman
authors.affiliation: Core Facility for Molecular Pathology and Biobanking, The Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands.
authors.forename: Dennis
authors.initials: D
authors.lastname: Peters
authors.affiliation: Division of Thoracic Oncology, The Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands.
authors.forename: Wieneke A
authors.initials: WA
authors.lastname: Buikhuisen
authors.affiliation: Division of Thoracic Oncology, The Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands.
authors.forename: Egbert F
authors.initials: EF
authors.lastname: Smit
authors.affiliation: Mouse Clinic for Cancer and Aging research Transgenic Core Facility, The Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands.
authors.forename: Colin
authors.initials: C
authors.lastname: Pritchard
authors.affiliation: Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands.
authors.forename: Miranda
authors.initials: M
authors.lastname: Cozijnsen
authors.affiliation: Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: van der Vliet
authors.affiliation: Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands.
authors.forename: John
authors.initials: J
authors.lastname: Zevenhoven
authors.affiliation: Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands.
authors.forename: Jan-Paul
authors.initials: JP
authors.lastname: Lambooij
authors.affiliation: Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands.
authors.forename: Natalie
authors.initials: N
authors.lastname: Proost
authors.affiliation: Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands.
authors.forename: Erwin
authors.initials: E
authors.lastname: van Montfort
authors.affiliation: Genomics Core Facility, The Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands.
authors.forename: Arno
authors.initials: A
authors.lastname: Velds
authors.affiliation: Mouse Clinic for Cancer and Aging research Transgenic Core Facility, The Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands. Electronic address: i.huijbers@nki.nl.
authors.forename: Ivo J
authors.initials: IJ
authors.lastname: Huijbers
authors.affiliation: Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands; Skolkovo Institute of Science and Technology, Moscow 143026, Russia. Electronic address: a.berns@nki.nl.
authors.forename: Anton
authors.initials: A
authors.lastname: Berns
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism; D049109:Cell Proliferation / Q000502:physiology; D004195:Disease Models, Animal; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D051839:NFI Transcription Factors / Q000378:metabolism*; D009362:Neoplasm Metastasis / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D055752:Small Cell Lung Carcinoma / Q000378:metabolism* / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D015820:Cadherins; D051839:NFI Transcription Factors; C110754:NFIB protein, human; C484683:Nfib protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53