Epithelial-mesenchymal transition can suppress major attributes of human epithelial tumor-initiating cells
Toni Celià-Terrassa, … , Pedro L. Fernández, Timothy M. Thomson
Toni Celià-Terrassa, … , Pedro L. Fernández, Timothy M. Thomson
Published April 16, 2012
Citation Information: J Clin Invest. 2012;122(5):1849-1868. https://doi.org/10.1172/JCI59218.
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Research Article Oncology

Epithelial-mesenchymal transition can suppress major attributes of human epithelial tumor-initiating cells

Abstract

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-mesenchymal 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 Snai1 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.

Authors

Toni Celià-Terrassa, Óscar Meca-Cortés, Francesca Mateo, Alexia Martínez de Paz, Nuria Rubio, Anna Arnal-Estapé, Brian J. Ell, Raquel Bermudo, Alba Díaz, Marta Guerra-Rebollo, Juan José Lozano, Conchi Estarás, Catalina Ulloa, Daniel ρlvarez-Simón, Jordi Milà, Ramón Vilella, Rosanna Paciucci, Marian Martínez-Balbás, Antonio García de Herreros, Roger R. Gomis, Yibin Kang, Jerónimo Blanco, Pedro L. Fernández, Timothy M. Thomson

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Figure 13

Expression of a self-renewal gene network active in PC-3/Mc cells is associated with more advanced stages of prostate cancer.

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Expression of a self-renewal gene network active in PC-3/Mc cells is ...
(A) GSEA on an expression data set for 150 prostate cancer samples (45) showing a significant enrichment of the M geneset (genes of the ESC module [ref. 13] enriched in PC-3/Mc cells) in metastases relative to primary tumors, and in T3 and T4 stage primary tumors relative to T1 and T2 stage primary tumors. Pearson’s correlation was applied to determine linear relationships between gene profiles and 3 phenotypes (class 1: metastatic; class 2: T3 and T4 stage primary; class 3: T1 and T2 stage primary) taken as continuous variables. (B). Heat map illustrating the relative expression levels for the 70 genes of the M gene set. Samples are ordered as primary tumors with stages T1 or T2, stages T3 or T4, or metastases (M). (C) Ninety-four cases of prostate cancer were analyzed for SOX2 expression by immunohistochemistry. Positive cases contained at least 10% of cells with nuclear SOX2 staining. *P < 0.05, between the frequencies of SOX2-positive cases in stages T2A and T2C versus and stage T3A and T3B tumors. (D) In some lymph node metastases, but in none of the 94 primary tumors, all visible tumor cells were strongly positive for nuclear SOX2, and stronger SOX2 expression correlated with stronger E-cadherin expression. Right: a second metastatic sample with a more heterogeneous and weaker nuclear SOX2 staining of tumor cells displays weaker membrane E-cadherin staining. Scale bars: 100 μm.