A role for partial epithelial-to-mesenchymal transition in enabling stemness in homeostasis and cancer.

Stem cells have self-renewal capacities and the ability to give rise to differentiated cells thereby sustaining tissues during homeostasis and injury. This structural hierarchy extends to tumours which harbor stem-like cells deemed cancer stem cells that propagate the tumour and drive metastasis and relapse. The process of epithelial-to-mesenchymal transition (EMT), which plays an important role in development and cancer cell migration, was shown to be correlated with stemness in both homeostasis and cancer indicating that stemness can be acquired and is not necessarily an intrinsic trait. Nowadays it is experimentally proven that the activation of an EMT program does not necessarily drive cells towards a fully mesenchymal phenotype but rather to hybrid E/M states. This review offers the latest advances in connecting the EMT status and stem-cell state of both non-transformed and cancer cells. Recent literature clearly shows that hybrid EMT states have a higher probability of acquiring stem cell traits. The position of a cell along the EMT-axis which coincides with a stem cell-like state is known as the stemness window. We show how the original EMT-state of a cell dictates the EMT/MET inducing programmes required to reach stemness. Lastly we present the mechanism of stemness regulation and the regulatory feedback loops which position cells at a certain EMT state along the EMT axis.

Intrinsic Balance between ZEB Family Members Is Important for Melanocyte Homeostasis and Melanoma Progression.

It has become clear that cellular plasticity is a main driver of cancer therapy resistance. Consequently, there is a need to mechanistically identify the factors driving this process. The transcription factors of the zinc-finger E-box-binding homeobox family, consisting of ZEB1 and ZEB2, are notorious for their roles in epithelial-to-mesenchymal transition (EMT). However, in melanoma, an intrinsic balance between ZEB1 and ZEB2 seems to determine the cellular state by modulating the expression of the master regulator of melanocyte homeostasis, microphthalmia-associated transcription factor (MITF). ZEB2 drives MITF expression and is associated with a differentiated/proliferative melanoma cell state. On the other hand, ZEB1 is correlated with low MITF expression and a more invasive, stem cell-like and therapy-resistant cell state. This intrinsic balance between ZEB1 and ZEB2 could prove to be a promising therapeutic target for melanoma patients. In this review, we will summarise what is known on the functional mechanisms of these transcription factors. Moreover, we will look specifically at their roles during melanocyte-lineage development and homeostasis. Finally, we will overview the current literature on ZEB1 and ZEB2 in the melanoma context and link this to the 'phenotype-switching' model of melanoma cellular plasticity.