Functional Balance between TCF21-Slug defines phenotypic plasticity and sub-classes in high-grade serous ovarian cancer

Cellular plasticity and transitional phenotypes add to complexities of cancer metastasis initiated by single cell epithelial to mesenchymal transition or cooperative cell migration (CCM). We identified novel regulatory cross-talks between Tcf21 and Slug in mediating phenotypic and migration plasticity in high-grade serous ovarian adenocarcinoma. Live imaging discerned CCM as being achieved either through rapid cell proliferation or sheet migration. Transitional states were enriched over the rigid epithelial or mesenchymal phenotypes under conditions of environmental stresses. The Tcf21-Slug interplay identified in HGSC tumors through effective stratification of subtypes also contributed to class-switching in response to disease progression or therapy. Our study effectively provides a framework for understanding the relevance of cellular plasticity in situ as a function of two transcription factors.

Collective cell migration: leadership, invasion and segregation

A number of biological processes, such as embryo development, cancer metastasis or wound healing, rely on cells moving in concert. The mechanisms leading to the emergence of coordinated motion remain however largely unexplored. Although biomolecular signalling is known to be involved in most occurrences of collective migration, the role of physical and mechanical interactions has only been recently investigated. In this study, a versatile framework for cell motility is implemented in silico in order to study the minimal requirements for the coordination of a group of epithelial cells. We find that cell motility and cell–cell mechanical interactions are sufficient to generate a broad array of behaviours commonly observed in vitro and in vivo . Cell streaming, sheet migration and susceptibility to leader cells are examples of behaviours spontaneously emerging from these simple assumptions, which might explain why collective effects are so ubiquitous in nature. The size of the population and its confinement appear, in particular, to play an important role in the coordination process. In all cases, the complex response of the population can be predicted from the knowledge of the correlation length of the velocity field measured in the bulk of the epithelial layer. This analysis provides also new insights into cancer metastasis and cell sorting, suggesting, in particular, that collective invasion might result from an emerging coordination in a system where single cells are mechanically unable to invade.