title: Obligate progression precedes lung adenocarcinoma dissemination.
abstract: Despite its clinical importance, very little is known about the natural history and molecular underpinnings of lung cancer dissemination and metastasis. Here, we used a genetically engineered mouse model of metastatic lung adenocarcinoma in which cancer cells are fluorescently marked to determine whether dissemination is an inherent ability or a major acquired phenotype during lung adenocarcinoma metastasis. We find very little evidence for dissemination from oncogenic KRAS-driven hyperplasias or most adenocarcinomas. p53 loss is insufficient to drive dissemination but rather enables rare cancer cells in a small fraction of primary adenocarcinomas to gain alterations that drive dissemination. Molecular characterization of disseminated tumor cells indicates that downregulation of the transcription factor Nkx2-1 precedes dissemination. Finally, we show that metastatic primary tumors possess a highly proliferative subpopulation of cells with characteristics matching those of disseminating cells. We propose that dissemination is a major hurdle during the natural course of lung adenocarcinoma metastasis.
  
  
  CONCLUSIONS
  Because of its aggressively metastatic nature, lung cancer is the top cancer killer of both men and women in the United States. We show that, unlike in other cancer types, lung cancer dissemination is a major initial barrier to metastasis. Our findings provide insight into the effect of p53 deficiency and downregulation of Nkx2-1 during lung adenocarcinoma progression.
authors.affiliation: Authors' Affiliations:Cancer Biology Program; Departments of.
authors.forename: Deborah R
authors.initials: DR
authors.lastname: Caswell
authors.affiliation: Genetics and.
authors.forename: Chen-Hua
authors.initials: CH
authors.lastname: Chuang
authors.affiliation: Authors' Affiliations:Cancer Biology Program; Departments of.
authors.forename: Dian
authors.initials: D
authors.lastname: Yang
authors.affiliation: Genetics and.
authors.forename: Shin-Heng
authors.initials: SH
authors.lastname: Chiou
authors.affiliation: Genetics and.
authors.forename: Shashank
authors.initials: S
authors.lastname: Cheemalavagu
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Caroline
authors.initials: C
authors.lastname: Kim-Kiselak
authors.affiliation: Pathology; and.
authors.forename: Andrew
authors.initials: A
authors.lastname: Connolly
authors.affiliation: Authors' Affiliations:Cancer Biology Program; Departments of Genetics and Pathology; and Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California; and mwinslow@stanford.edu.
authors.forename: Monte M
authors.initials: MM
authors.lastname: Winslow
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology*; D009374:Neoplasms, Experimental; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: C000614414:Nkx2-1 protein, mouse; D009687:Nuclear Proteins; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53
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