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 (eg. adhesion) and mesenchymal (eg. 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 undergone 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-stroma 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 introduce a phenomenological continuum model for the mode III dynamic fracture that is based on the phase-field methodology used extensively to model interfacial pattern formation. We couple a scalar field, which distinguishes between “broken” and “unbroken” states of the system, to the displacement field in a way that consistently includes both macroscopic elasticity and a simple rotationally invariant short-scale description of breaking. We report two-dimensional simulations that yield steady-state crack motion in a strip geometry above the Griffith threshold.

In nature, microorganisms must often cope with hostile environmental conditions. To do so they have developed sophisticated cooperative behaviour and intricate communication capabilities, such as: direct cell-cell physical interactions via extra-membrane polymers, collective production of extracellular 'wetting' fluid for movement on hard surfaces, long range chemical signalling such as quorum sensing and chemotactic (bias of movement according to gradient of chemical agent) signalling, collective activation and deactivation of genes and even exchange of genetic material. Utilizing these capabilities, the colonies develop complex spatio-temporal patterns in response to adverse growth conditions. We present a wealth of beautiful patterns formed during colony development of various microorganisms and for different environmental conditions. Invoking ideas from pattern formation in non-living systems and using 'generic' modelling we are able to reveal novel survival strategies which account for the salient features of the evolved patterns. Using the models, we demonstrate how communication leads to self-organization via cooperative behaviour of the cells. In this regard, pattern formation in microorganisms can be viewed as the result of the exchange of information between the micro-level (the individual cells) and the macro-level (the colony). As such, a full understanding of bacterial behaviour must focus simultaneously on individual cell responses and overall colony organization.

Significance: Epithelial–mesenchymal transitions play crucial roles in embryonic development, wound healing, and cancer metastasis. It is clearly of interest to quantitatively understand the core circuitry that takes input from the cell’s environment to perform this cell-fate decision. We devised a unique model of the microRNA (miR)-based coupled chimeric modules underlying this core circuit; this effort utilizes a unique theoretical framework for treating miR dynamics. We show that the miR-200/ZEB module functions as a ternary switch, allowing not only for the epithelial and mesenchymal phenotypes but also for a hybrid phenotype with mixed characteristics of collective cell migration, as seen in branching morphogenesis and wound closure. Our results provide valuable clues on how to control and reverse epithelial–hybrid–mesenchymal transitions.

Tumor budding is a histological phenomenon encountered in various cancers, whereby individual malignant cells and/or small clusters of malignant cells are seen in the tumor stroma. Postulated to be mirror epithelial-mesenchymal transition, tumor budding has been associated with poor cancer outcomes. However, the vast heterogeneity in its exact definition, methodology of assessment, and patient stratification need to be resolved before it can be routinely used as a standardized prognostic feature. Here, we discuss the heterogeneity in defining and assessing tumor budding, its clinical significance across multiple cancer types, and its prospective implementation in clinical practice. Next, we review the emerging evidence about partial, rather than complete, epithelial-mesenchymal phenotype at the tumor bud level, and its connection with tumor proliferation, quiescence, and stemness. Finally, based on recent literature, indicating a co-expression of epithelial and mesenchymal markers in many tumor buds, we posit tumor budding to be a manifestation of this hybrid epithelial/mesenchymal phenotype displaying collective cell migration.