Epithelial-to-Mesenchymal Transition in the Light of Plasticity and Hybrid E/M States

Abstract

Epithelial-to-mesenchymal transition (EMT) is a cellular program which leads to cells losing epithelial features, including cell polarity, cell–cell adhesion and attachment to the basement membrane, while gaining mesenchymal characteristics, such as invasive properties and stemness. This program is involved in embryogenesis, wound healing and cancer progression. Over the years, the role of EMT in cancer progression has been heavily debated, and the requirement of this process in metastasis even has been disputed. In this review, we discuss previous discrepancies in the light of recent findings on EMT, plasticity and hybrid E/M states. Moreover, we highlight various tumor microenvironmental cues and cell intrinsic signaling pathways that induce and sustain EMT programs, plasticity and hybrid E/M states. Lastly, we discuss how recent findings on plasticity, especially on those that enable cells to switch between hybrid E/M states, have changed our understanding on the role of EMT in cancer metastasis, stemness and therapy resistance.

Single‐Cell RNA‐seq Reveals a Developmental Hierarchy Super‐Imposed Over Subclonal Evolution in the Cellular Ecosystem of Prostate Cancer

“…Moreover, it was reported that cells in an intermediate state along the epithelial–mesenchymal axis are plastic, invasive, and highly metastatic. [ 29 ] Whereas with limited number of cases and insufficient follow‐up period in current cohort, we further validated the role of tumor cell transcriptional plasticity in patients’ outcome in TCGA cohorts. Given that the role of tumor microenvironmental cues in shaping tumor cell plasticity, indeed we identified both a higher proportion of subtype 0 tumor cells and the higher cellular diversity of the tumor ecosystem were associated with a poorer outcome ( Figure 7 ).…”

Mini-Review: Can the Metastatic Cascade Be Inhibited by Targeting CD147/EMMPRIN to Prevent Tumor Recurrence?

“…Metastasis is a multi-step process that begins with a change in the epithelial phenotype of the cells, a process known as the Epithelial-To-Mesenchymal Transition (EMT). EMT promotes the detachment of some tumor cells, increases their motility and changes their phenotype into a mesenchymal, spindle-like morphology ( 5 ). This increases their invasiveness and ability to resist different drugs ( 6 , 7 ).…”

“…The increased motility allows a cell to pave its way through the extracellular matrix (ECM), intravasate into a lymphatic or blood vessel to become a circulating tumor cell (CTC), and then extravasate in a regional lymph node or a distant tissue as a disseminated tumor cell (DTC) ( 8 ). However, while every metastasizing cell must undergo EMT, it is important to remember that EMT is not a binary process, and cancer cells are found in many hybrid forms along the epithelial/mesenchymal axis (hybrid E/M cells), having both epithelial and mesenchymal features that endow them with the plasticity to adjust to different microenvironments ( 5 , 9 ). The DTCs that are lodged in the remote organ, either as single cells or as clusters of a few cells, may remain in a latent or quiescent state for years or decades (dormancy), undetected by imaging techniques, until they suddenly start proliferating (colonization).…”

Epithelial-to-Mesenchymal Transition Drives Invasiveness of Breast Cancer Brain Metastases

“…The migratory and infiltrative behaviors of BC cells that escape primary tumors have been extensively studied [8][9][10][11][12][13]. It is generally accepted that in order to become invasive, cells in the primary tumor hijack the developmental program known as EMT [14][15][16][17][18][19][20][21][22][23][24]. For instance, we and others previously used intravital microscopy to show that cells that escape from primary breast tumor and invade the healthy stroma undergo EMT [25][26][27][28].…”

“…During EMT, cells downregulate the expression of epithelial markers such as the cell-cell adhesion molecule E-cadherin (E-cad), thereby losing cell polarity and cell-cell adhesion. In parallel, cells undergoing EMT acquire mesenchymal markers that drive stemness and invasiveness such as Zeb1 and Twist [14,18,21,[29][30][31][32][33][34]. To date, the role of EMT in BC has mainly been studied in the context of cancer cells disseminating from the primary tumor and during the outgrowth of extracranial metastases, but the existence and functions of EMT in BCBM remain unknown.…”