期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 122, 期 5, 页码 1849-1868出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI59218
关键词
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资金
- CSIC
- Juan de la Cierva from the Ministerio de Ciencia e Innovacion (MICINN)
- MICINN [SAF2008-04136-C02-01, SAF2011-24686, FIS-PI080274, SAF2007-62691]
- Agencia de Gestio d'Ajuts Universitaris i de Recerca [2009SGR1482]
- Agencia Espanola de Cooperacion Internacional y Desarrollo [A/023859/09]
- Xarxa de Referencia en Biotecnologia
- Fondo de Investigaciones de la Seguridad Social [PI080274]
- Spanish National Biobank Network
- Instituto de Salud Carlos III [ISCIII-RETIC RD06/0020]
- Xarxa de Bancs de Tumours de Catalunya-Pla Director d'Oncologia
- Fondo Europeo de Desarrollo Regional (FEDER) - Union Europea
- BBVA Foundation
- ICREA Funding Source: Custom
Malignant progression in cancer requires populations of tumor-initiating cells (TICs) endowed with unlimited self renewal, survival under stress, and establishment of distant metastases. Additionally, the acquisition of invasive properties driven by epithelial-mesenchyrnal transition (EMT) is critical for the evolution of neoplastic cells into fully metastatic populations. Here, we characterize 2 human cellular models derived from prostate and bladder cancer cell lines to better understand the relationship between TIC and EMT programs in local invasiveness and distant metastasis. The model tumor subpopulations that expressed a strong epithelial gene program were enriched in highly metastatic TICs, while a second subpopulation with stable mesenchymal traits was impoverished in TICs. Constitutive overexpression of the transcription factor Snail in the epithelial/TIC-enriched populations engaged a mesenchymal gene program and suppressed their self renewal and metastatic phenotypes. Conversely, knockdown of EMT factors in the mesenchymal-like prostate cancer cell subpopulation caused a gain in epithelial features and properties of TICs. Both tumor cell subpopulations cooperated so that the nonmetastatic mesenchymal-like prostate cancer subpopulation enhanced the in vitro invasiveness of the metastatic epithelial subpopulation and, in vivo, promoted the escape of the latter from primary implantation sites and accelerated their metastatic colonization. Our models provide new insights into how dynamic interactions among epithelial, self-renewal, and mesenchymal gene programs determine the plasticity of epithelial TICs.
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