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Register a new userSwitch-like enhancement of epithelial-mesenchymal transition by YAP through feedback regulation of WT1 and small Rho-family GTPases
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Collective cell migration is a hallmark of developmental and patho-physiological states, including wound healing and invasive cancer growth. The integrity of the expanding epithelial sheets can be influenced by extracellular cues, including cell-cell and cell-matrix interactions. We show the nano-scale topography of the extracellular matrix underlying epithelial cell layers can have a strong effect on the speed and morphology of the fronts of the expanding sheet triggering epithelial-mesenchymal transition (EMT). We further demonstrate that this behavior depends on the mechano-sensitivity of the transcription regulator YAP and two new feedback cross-regulation mechanisms: through Wilms Tumor-1 and E-cadherin, loosening cell-cell contacts, and through Rho GTPase family proteins, enhancing cell migration. These YAP-dependent regulatory feedback loops result in a switch-like change in the signaling and expression of EMT-related markers, leading to a robust enhancement in invasive epithelial sheet expansion, which might lead to a poorer clinical outcome in renal and other cancers.
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Cancer cells have the plasticity to adjust their metabolic phenotypes for survival and metastasis. During metastasis, a developmental program known as the epithelial-mesenchymal transition (EMT) plays a critical role. There is extensive cross-talk between metabolism and EMT, but how this leads to coordinated physiological changes is still uncertain. The elusive connection between metabolism and EMT compromises the efficacy of metabolic therapies targeting metastasis. In this review, we aim for clarifying causation between metabolism and EMT based on recent experimental studies and propose integrated theoretical-experimental efforts to better understand the coupled decision-making of metabolism and EMT.
Understanding cell-fate decisions during tumorigenesis and metastasis is a major challenge in modern cancer biology. One canonical cell-fate decision that cancer cells undergo is Epithelial-to-Mesenchymal Transition (EMT) and its reverse Mesenchymal-to-Epithelial Transition (MET). While transitioning between these two phenotypes - epithelial and mesenchymal - cells can also attain a hybrid epithelial/mesenchymal (i.e. partial or intermediate EMT) phenotype. Cells in this phenotype have mixed epithelial (e.g. adhesion) and mesenchymal (e.g. migration) properties, thereby allowing them to move collectively as clusters of Circulating Tumor Cells (CTCs). If these clusters enter the circulation, they can be more apoptosis-resistant and more capable of initiating metastatic lesions than cancer cells moving individually with wholly mesenchymal phenotypes, having undergo a complete EMT. Here, we review the operating principles of the core regulatory network for EMT/MET that acts as a three-way switch giving rise to three distinct phenotypes - epithelial, mesenchymal and hybrid epithelial/mesenchymal. We further characterize this hybrid E/M phenotype in terms of its capabilities in terms of collective cell migration, tumor-initiation, cell-cell communication, and drug resistance. We elucidate how the highly interconnected coupling between these modules coordinates cell-fate decisions among a population of cancer cells in the dynamic tumor, hence facilitating tumor-stoma interactions, formation of CTC clusters, and consequently cancer metastasis. Finally, we discuss the multiple advantages that the hybrid epithelial/mesenchymal phenotype have as compared to a complete EMT phenotype and argue that these collectively migrating cells are the primary bad actors of metastasis.
We present the epithelial-to-mesenchymal transition (EMT) from two perspectives: experimental/technological and theoretical. We review the state of the current understanding of the regulatory networks that underlie EMT in three physiological contexts: embryonic development, wound healing, and metastasis. We describe the existing experimental systems and manipulations used to better understand the molecular participants and factors that influence EMT and metastasis. We review the mathematical models of the regulatory networks involved in EMT, with a particular emphasis on the network motifs (such as coupled feedback loops) that can generate intermediate hybrid states between the epithelial and mesenchymal states. Ultimately, the understanding gained about these networks should be translated into methods to control phenotypic outcomes, especially in the context of cancer therapeutic strategies. We present emerging theories of how to drive the dynamics of a network toward a desired dynamical attractor (e.g. an epithelial cell state) and emerging synthetic biology technologies to monitor and control the state of cells.
We present a minimal motif model for transmembrane cell signaling. The model assumes signaling events taking place in spatially distributed nanoclusters regulated by a birth/death dynamics. The combination of these spatio-temporal aspects can be modulated to provide a robust and high-fidelity response behavior without invoking sophisticated modeling of the signaling process as a sequence of cascade reactions and fine-tuned parameters. Our results show that the fact that the distributed signaling events take place in nanoclusters with a finite lifetime regulated by local production is sufficient to obtain a robust and high-fidelity response.
We propose a multiscale chemo-mechanical model of cancer tumour development in an epithelial tissue. The model is based on transformation of normal cells into the cancerous state triggered by a local failure of spatial synchronisation of the circadian rhythm. The model includes mechanical interactions and chemical signal exchange between neighbouring cells, as well as division of cells and intercalation, and allows for modification of the respective parameters following transformation into the cancerous state. The numerical simulations reproduce different dephasing patterns - spiral waves and quasistationary clustering, with the latter being conducive to cancer formation. Modification of mechanical properties reproduces distinct behaviour of invasive and localised carcinoma.
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