An EpCAM/Trop2 mechanostat differentially regulates collective behaviour of human carcinoma cells.

EpCAM and its close relative Trop2 are well-known cell surface markers of carcinoma, but their potential role in cancer metastasis remains unclear. They are known, however, to downregulate myosin-dependent contractility, a key parameter involved in adhesion and migration. We investigate here the morphogenetic impact of the high EpCAM and Trop2 levels typically found in epithelial breast cancer cells, using spheroids of MCF7 cells as an in vitro model. Intriguingly, EpCAM depletion stimulated spheroid cohesive spreading, while Trop2 depletion had the opposite effect. Combining cell biological and biophysical approaches, we demonstrate that while EpCAM and Trop2 both contribute to moderate cell contractility, their depletions differentially impact on the process of "wetting" a substrate, here both matrix and neighboring cells, by affecting the balance of cortical tension at cell and tissue interfaces. These distinct phenotypes can be explained by partial enrichment at specific interfaces. Our data are consistent with the EpCAM-Trop2 pair acting as a mechanostat that tunes adhesive and migratory behaviours. Synopsis: Cell adhesion and cell cortex contractility are important determinants of the morphogenetic properties of solid tissues, including tumours. This study shows that EpCAM and Trop2, two closely related surface markers of carcinoma, play antagonistic roles, respectively opposing or favouring cohesion and collective migration of breast cancer cells. Both EpCAM or Trop2 repress myosin activity and cortical contractility. EpCAM tends to act preferentially on the cell cortex at free edges, Trop2 on matrix and cell adhesive contacts, subtly controlling the balance of tensions at interfaces. Consistently, the two molecules show differential enrichments at the corresponding cell cortices. MCF7 spheroids depleted of EpCAM extensively spread while remaining compact, while those depleted of Trop2 show lower cohesion and spreading than wild type spheroids. Effects of EpCAM and Trop2 can be accurately modelled based on the biophysical analogy with the phenomenon of wetting-dewetting. Two closely related cell surface proteins affect cortical tension in different domains and differentially regulate cell cluster cohesion and spreading. [ABSTRACT FROM AUTHOR]