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Register a new userTowards decoding the coupled decision-making of metabolism and epithelial-mesenchymal transition in cancer
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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.
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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.
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.
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.
Tumor metastasis is one of the main factors responsible for the high fatality rate of cancer. Metastasis can occur after malignant cells transition from the epithelial phenotype to the mesenchymal phenotype. This transformation allows cells to migrate via the circulatory system and subsequently settle in distant organs after undergoing the reverse transition from the mesenchymal to the epithelial phenotypes. The core gene regulatory network controlling these transitions consists of a system made up of coupled SNAIL/miRNA-34 and ZEB1/miRNA-200 subsystems. In this work, we formulate a mathematical model of the core regulatory motif and analyze its long-term behavior. We start by developing a detailed reaction network with 24 state variables. Assuming fast promoter and mRNA kinetics, we then show how to reduce our model to a monotone four-dimensional system. For the reduced system, monotone dynamical systems theory can be used to prove generic convergence to the set of equilibria for all bounded trajectories. The theory does not apply to the full model, which is not monotone, but we briefly discuss results for singularly-perturbed monotone systems that provide a tool to extend convergence results from reduced to full systems, under appropriate time separation assumptions.
Directed fibroblast migration is central to highly proliferative processes in regenerative medicine and developmental biology, such as wound healing and embryogenesis. However, the mechanisms by which single fibroblasts affect each others directional decisions, while chemotaxing in microscopic tissue pores, are not well understood. Therefore, we explored the effects of two types of relevant social interactions on fibroblast PDGF-BB-induced migration in microfluidic tissue-mimicking mazes: cell sequence and mitosis. Surprisingly, it was found that in both cases, the cells display behavior that is contradictory to the chemoattractant gradient established in the maze. In case of the sequence, the cells do not like to take the same path through the maze as their predecessor, when faced with a bifurcation. To the contrary, they tend to alternate - if a leading cell takes the shorter (steeper gradient) path, the cell following it chooses the longer (weaker gradient) path, and vice versa. Additionally, we found that when a mother cell divides, its two daughters go in opposite directions (even if it means migrating against the chemoattractant gradient and overcoming on-going cell traffic). Therefore, it is apparent that fibroblasts modify each others directional decisions in a manner that is counter-intuitive to what is expected from classical chemotaxis theory. Consequently, accounting for these effects could lead to a better understanding of tissue generation in vivo, and result in more advanced engineered tissue products in vitro.
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