Tracking the intermediate stages of epithelial-mesenchymal transition in epithelial stem cells and cancer

Abstract

Epithelial-mesenchymal transition (EMT) is an essential developmental program that becomes reactivated in adult tissues to promote the progression of cancer. EMT has been largely studied by examining the beginning epithelial state or the ending mesenchymal state without studying the intermediate stages. Recent studies using trophoblast stem (TS) cells paused in EMT have defined the molecular and epigenetic mechanisms responsible for modulating the intermediate "metastable" stages of EMT. Targeted inactivation of MAP3K4, knockdown of CBP, or overexpression of SNAI1 in TS cells induced similar metastable phenotypes. These TS cells exhibited epigenetic changes in the histone acetylation landscape that cause loss of epithelial maintenance while preserving self-renewal and multipotency. A similar phenotype was found in claudin-low breast cancer cells with properties of EMT and stemness. This intersection between EMT and stemness in TS cells and claudin-low metastatic breast cancer demonstrates the usefulness of developmental EMT systems to understand EMT in cancer.

Figure 1

Comparison of EMT subtypes in development and cancer metastasis. The first developmental EMT that occurs during implantation of the blastocyst into the uterine epithelium (left part) and EMT associated with the metastatic progression of cancer (right part) are shown. MET indicates mesenchymal-epithelial transition.

Figure 2

Characteristics of intermediate stages of EMT in trophoblast stem cells. TS^WT and TS^KI4 cells were isolated from wild-type or MAP3K4 kinase-inactive conceptuses, respectively. TS^shCBP cells are TS^WT cells expressing CBP shRNA. TS^SNAI1 cells are TS^WT cells overexpressing SNAI1. TS^WT, TS^KI4, TS^shCBP and TS^SNAI1 cells are cultured under non-differentiating conditions in FGF4. T^INV cells are invasive trophoblasts cultured for four days under differentiating conditions and isolated from Matrigel-coated transwell invasion chambers. The ⁺ symbol indicates presence of the trait; the − symbol indicates absence of the trait. The quantity of ⁺ symbols indicates the relative degree of presence of the trait.