Abstract
A key regulator of collective cell migrations, which drive development and cancer metastasis, is substrate stiffness. Increased substrate stiffness promotes migration and is controlled by Myosin. Using Drosophila border cell migration as a model of collective cell migration, we identify, for the first time, that the actin bundling protein Fascin limits Myosin activity in vivo. Loss of Fascin results in: increased activated Myosin on the border cells and their substrate, the nurse cells; decreased border cell Myosin dynamics; and increased nurse cell stiffness as measured by atomic force microscopy. Reducing Myosin restores on-time border cell migration in fascin mutant follicles. Further, Fascin's actin bundling activity is required to limit Myosin activation. Surprisingly, we find that Fascin regulates Myosin activity in the border cells to control nurse cell stiffness to promote migration. Thus, these data shift the paradigm from a substrate stiffness-centric model of regulating migration, to uncover that collectively migrating cells play a critical role in controlling the mechanical properties of their substrate in order to promote their own migration. This understudied means of mechanical regulation of migration is likely conserved across contexts and organisms, as Fascin and Myosin are common regulators of cell migration.
Highlights
Cell migration is an essential process driving both development and cancer metastasis.During these processes, cells often migrate as groups or collectives, rather than single cells (Friedl and Gilmour, 2009)
Myosin generates forces in the nurse cells that push upon the border cells, causing the border cells to activate Myosin and stiffen (Aranjuez et al, 2016), suggesting that the nurse cells control the stiffness of the border cell cluster
We hypothesized that Fascin may regulate Myosin activity in the Drosophila follicle, the nurse cells, to promote border cell migration
Summary
Cell migration is an essential process driving both development and cancer metastasis. During these processes, cells often migrate as groups or collectives, rather than single cells (Friedl and Gilmour, 2009). Many collective cell migrations occur in an invasive manner with the group of cells migrating between other cells or through basement membranes (Chang et al, 2019). The environment puts mechanical forces on the migrating cells, causing them to respond by changing their shape and stiffness, and by modifying properties of their environment, such as extracellular matrix (ECM) composition (Aguilar-Cuenca et al, 2014; Gasparski et al, 2017; Eble and Niland, 2019). Stiffness has emerged as a critical regulator of collective cell migration
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