Data from Obligate Progression Precedes Lung Adenocarcinoma Dissemination

Abstract

<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>

Combinatorialin vivogenome editing identifies widespread epistasis during lung tumorigenesis

“…The analysis of combinatorial genetic alterations on tumorigenesis in vivo using conventional Cre/Lox-based systems has uncovered important genetic interactions between tumor suppressor genes 31 . However, conventional in vivo cancer models are not sufficiently scalable to generate a broad understanding of genetic interactions between tumor suppressor genes that drive carcinogenesis 18,27,28,32 . CRISPR/Cas9-mediated somatic genome editing in somatic cells has increased the scale of in vivo functional analyses, and integration with tumor barcoding has enabled precise and multiplexed quantification of tumor initiation and growth 23,[33][34][35] .…”