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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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 7

E-cadherin is required for anchorage-independent growth and lung colonization of PC-3/Mc cells.

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E-cadherin is required for anchorage-independent growth and lung ...
(A) Knockdown of E-cadherin in PC-3/Mc cells downregulated SOX2 and MYC. Controls were puromycin-selected PC-3/Mc cells bearing pLK0-scrambled lentiviral vector. (B) Knockdown of E-cadherin enhanced the invasiveness of PC-3/Mc cells. (C) Knockdown of E-cadherin inhibited the spheroid-forming potential of PC-3/Mc cells. (D) Knockdown of E-cadherin in PC-3/Mc cells caused a modest downregulation of self-renewal/pluripotency genes. Relative transcript levels are represented as the log10 of ratios between experimental and control cells of 2–ΔΔCp real-time PCR values. Controls were PC-3/Mc cells bearing pLK0-scrambled vector. (E) Knockdown of E-cadherin in PC-3/Mc cells detected by indirect immunofluorescence. Scale bars: 20 μm. (F) Knockdown of E-cadherin in PC-3/Mc cells inhibited their lung colonization after i.v. injection into SCID mice. The Kaplan-Meier plot reflects the actuarial numbers of lung colonization–free mice. (G) Overexpression of E-cadherin in PC-3/S cells caused a downregulation of FN1. (H) Overexpression of E-cadherin strongly inhibited the invasiveness of PC-3/S cells. (I) Overexpression of E-cadherin strongly enhanced the spheroid-forming potential of PC-3/S cells. (J) Overexpression of E-cadherin strongly enhanced the tumorigenicity of PC-3/S cells. PC-3/S-CDH1 and control cells (5 × 105) were implanted i.m. in the hind limbs of male Swiss-nude mice and tumor growth monitored with a caliper. (K) Overexpression of E-cadherin induced a moderate upregulation of self-renewal/pluripotency genes and a moderate downregulation of mesenchymal genes. Asterisk in K shows E-cadherin levels determined in murine E-cadherin–overexpressing cells reflect the exogenous transcripts, quantified with mouse-specific primers and probes (values are off scale). Results are expressed as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001.