title: Different thresholds of ZEB1 are required for Ras-mediated tumour initiation and metastasis.
abstract: Ras pathway mutation is frequent in carcinomas where it induces expression of the transcriptional repressor ZEB1. Although ZEB1 is classically linked to epithelial-mesenchymal transition and tumour metastasis, it has an emerging second role in generation of cancer-initiating cells. Here we show that Ras induction of ZEB1 is required for tumour initiation in a lung cancer model, and we link this function to repression Pten, whose loss is critical for emergence of cancer-initiating cells. These two roles for ZEB1 in tumour progression can be distinguished by their requirement for different levels of ZEB1. A lower threshold of ZEB1 is sufficient for cancer initiation, whereas further induction is necessary for tumour metastasis.
authors.affiliation: 1] Molecular Targets Program, James Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, Kentucky 40202, USA [2] Department of Ophthalmology and Visual Sciences, University of Louisville Health Sciences Center, Louisville, Kentucky 40202, USA [3] Birth Defects Center, University of Louisville Health Sciences Center, Louisville, Kentucky 40202, USA.
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Louisville Health Sciences Center, Louisville, Kentucky 40202, USA.
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Lu
authors.affiliation: 1] Department of Ophthalmology and Visual Sciences, University of Louisville Health Sciences Center, Louisville, Kentucky 40202, USA [2] College of Agriculture and Biotechnology, Zejiang University, Zejiang 310058, China.
authors.forename: Li
authors.initials: L
authors.lastname: Huang
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Louisville Health Sciences Center, Louisville, Kentucky 40202, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Louisville Health Sciences Center, Louisville, Kentucky 40202, USA.
authors.forename: Guomin
authors.initials: G
authors.lastname: Jiang
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Louisville Health Sciences Center, Louisville, Kentucky 40202, USA.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Dean
authors.affiliation: Molecular Targets Program, James Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, Kentucky 40202, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Clem
authors.affiliation: Molecular Targets Program, James Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, Kentucky 40202, USA.
authors.forename: Sucheta
authors.initials: S
authors.lastname: Telang
authors.affiliation: Molecular Targets Program, James Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, Kentucky 40202, USA.
authors.forename: Alfred B
authors.initials: AB
authors.lastname: Jenson
authors.affiliation: 1] Department of Pathology, Centro de Diagnóstico Biomédico (CDB) Hospital Clínic, University of Barcelona, Barcelona 08036, Spain [2] Tumor Bank-Biobank, IDIBAPS, Barcelona 08036, Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: Cuatrecasas
authors.affiliation: Molecular Targets Program, James Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, Kentucky 40202, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Chesney
authors.affiliation: Department of Periodontics, Endodontics, and Dental Hygiene, University of Louisville, Louisville, Kentucky 40202, USA.
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Darling
authors.affiliation: 1] Molecular Targets Program, James Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, Kentucky 40202, USA [2] Group of Transcriptional Regulation of Gene Expression, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain [3] ICREA, Barcelona 08010, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Postigo
authors.affiliation: 1] Molecular Targets Program, James Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, Kentucky 40202, USA [2] Department of Ophthalmology and Visual Sciences, University of Louisville Health Sciences Center, Louisville, Kentucky 40202, USA [3] Birth Defects Center, University of Louisville Health Sciences Center, Louisville, Kentucky 40202, USA.
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Dean
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000236:Adenoma / Q000235:genetics* / Q000473:pathology; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009362:Neoplasm Metastasis; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; D012333:RNA, Messenger; C519422:ZEB1 protein, mouse; D000071799:Zinc Finger E-box-Binding Homeobox 1; D058539:Phosphatidylinositol 3-Kinase; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)