From Stanford U: Obligate progression precedes lung adenocarcinoma dissemination

Cancer Discov. 2014 Apr 16. [Epub ahead of print]

Obligate progression precedes lung adenocarcinoma dissemination.

Caswell DR1, Chuang CH, Yang D, Chiou SH, Cheemalavagu S, Kim-Kiselak C, Connolly A, Winslow MM.

Author information

• 11Genetics, Stanford University.

Abstract

Despite its clinical importance, very little is known about the natural history and molecular underpinnings of lung cancer dissemination and metastasis. Here we employed 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. Molecularcharacterization of disseminated tumors cells indicates that down-regulation of the transcription factor Nkx2-1 precedes dissemination. Finally, we show that metastatic primary tumors possess a highly proliferative sub-population 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.