Obligate progression precedes lung adenocarcinoma dissemination

Deborah R. Caswell, Chen Hua Chuang, Dian Yang, Shin Heng Chiou, Shashank Cheemalavagu, Caroline Kim-Kiselak, Andrew Connolly, Monte M. Winslow

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)781-789
Number of pages9
JournalCancer Discovery
Volume4
Issue number7
DOIs
StatePublished - Jul 2014
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology

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