American Association for Cancer Research
21598290cd130862-sup-supp_fig_3.pdf (91.95 kB)

Supplementary Figure 3 from Obligate Progression Precedes Lung Adenocarcinoma Dissemination

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journal contribution
posted on 2023-04-03, 20:44 authored by Deborah R. Caswell, Chen-Hua Chuang, Dian Yang, Shin-Heng Chiou, Shashank Cheemalavagu, Caroline Kim-Kiselak, Andrew Connolly, Monte M. Winslow

PDF file 91K, KPT-Late mice with lung tumor initiated with adenoviral or lentiviral Cre vectors have similar progression and metastasis



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

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