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

TLDR

Malignant progression requires tumor‑initiating cells with unlimited self‑renewal, stress survival, and metastatic capacity, and epithelial‑mesenchymal transition is essential for acquiring invasive properties. The study characterizes two human prostate and bladder cancer cell models to investigate how tumor‑initiating and EMT programs interact in local invasiveness and distant metastasis. Using these models, the authors manipulated EMT regulators—overexpressing Snai1 in epithelial/TIC‑enriched cells and knocking down EMT factors in mesenchymal‑like cells—to assess effects on self‑renewal, metastatic potential, and epithelial traits. Epithelial‑gene‑programmed subpopulations were enriched for metastatic TICs, mesenchymal‑trait subpopulations were depleted of TICs, Snai1 overexpression activated a mesenchymal program that suppressed self‑renewal and metastasis, EMT‑factor knockdown restored epithelial features and TIC properties, and the two subpopulations cooperated to enhance invasiveness and accelerate metastatic colonization, illustrating that dynamic interactions among epithelial, self‑renewal, and mesenchymal programs dictate TIC plasticity.

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.