  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.
