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. Molecular characterization 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.

A 50-year-old woman with a history of Crohn’s disease treated with adalimumab presented with left hand pain and duskiness. Angiogram showed non-filling of the radial and digital arteries of the hand. Antiphospholipid antibody testing was positive, leading to a diagnosis of antitumour necrosis factor-induced antiphospholipid syndrome. Adalimumab was discontinued, and she was treated with the vitamin K antagonist warfarin and low-dose aspirin. Upon resolution of the antiphospholipid antibodies, she was transitioned to aspirin alone without recurrence of thrombosis.

<div>Abstract<p>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.</p><p><b>Significance:</b> 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. <i>Cancer Discov; 4(7); 781–9. ©2014 AACR</i>.</p><p>This article is highlighted in the In This Issue feature, p. 745</p></div>

<p>PDF file 105K, Generation and validation of the multicolor Motley reporter allele</p>

<p>PDF file 128K, KT-Early and KT-Late mice have high total tumor burden</p>