Stem-Cell-like Properties and Epithelial Plasticity Arise as Stable Traits after Transient Twist1 Activation

Abstract

Master regulators of the epithelial-mesenchymal transition such as Twist1 and Snail1 have been implicated in invasiveness and the generation of cancer stem cells, but their persistent activity inhibits stem-cell-like properties and the outgrowth of disseminated cancer cells into macroscopic metastases. Here, we show that Twist1 activation primes a subset of mammary epithelial cells for stem-cell-like properties, which only emerge and stably persist following Twist1 deactivation. Consequently, when cells undergo a mesenchymal-epithelial transition (MET), they do not return to their original epithelial cell state, evidenced by acquisition of invasive growth behavior and a distinct gene expression profile. These data provide an explanation for how transient Twist1 activation may promote all steps of the metastatic cascade; i.e., invasion, dissemination, and metastatic outgrowth at distant sites.

EMT, CSCs, and drug resistance: the mechanistic link and clinical implications

“…Thus, while EMT-programme activation in the otherwise-epithelial carcinoma cells generally results in an enhanced potential for tumorigenesis, full activation of the entire EMT programme — that is, complete transition to a mesenchymal cell type — has been found to be detrimental to tumorigenic activity 88,148,187 . Moreover, under certain conditions, CSCs can undergo phenotypic drift, thus losing mesenchymal traits while maintaining their tumorigenic activity 146,147 .…”

Distinctive properties of metastasis-initiating cells

“…Recent studies using nonmalignant cells suggest that sequential EMT and MET events increase the pluripotent state in keratinocytes and fibroblasts Unternaehrer et al 2014). Other studies have validated this in mammary epithelial cells by transiently expressing TWIST1 (Schmidt et al 2015). Although no experimental evidence supporting this hypothesis has been provided in the context of cancer metastasis, this model correlates with the natural sequence of events occurring during metastasis, where primary tumor cells undergo EMT to escape from the primary site and survive and later revert by MET to colonize distant tissues (Tsai et al 2012).…”

“…Therefore, it is important to consider distinct EMT drivers and target cell populations when analyzing results from EMT experiments. Further complicating the analysis, the reversion of EMT (MET) can also induce stem cell-like properties and increase metastasis initiation of epithelial-like CSCs, as has been documented in multiple recent studies (Celia-Terrassa et al 2012;Ocana et al 2012;Stankic et al 2013;Beck et al 2015;Schmidt et al 2015). Based on these results, CSCs can exist in both an epithelial-like or a mesenchymallike transitional state, while cells fixed at extreme epithelial or mesenchymal states lose plasticity and the associated stem cell activities (Nieto 2013;Oskarsson et al 2014).…”

Cancer Stem Cells: Basic Concepts and Therapeutic Implications

“…EMT TF expression may be dynamically regulated during tumor progression. Twist1 primes a subset of mammary epithelial cells for SC-like properties, which emerge only when Twist1 has been downregulated, whereas sustained Twist1 expression locks tumor cells into their EMT state (101).…”