Interplay of RhoA and mechanical forces in collective cell migration driven by leader cells

Abstract

The leading front of a collectively migrating epithelium often destabilizes into multicellular migration fingers where a cell initially similar to the others becomes a leader cell while its neighbours do not alter. The determinants of these leader cells include mechanical and biochemical cues, often under the control of small GTPases. However, an accurate dynamic cartography of both mechanical and biochemical activities remains to be established. Here, by mapping the mechanical traction forces exerted on the surface by MDCK migration fingers, we show that these structures are mechanical global entities with the leader cells exerting a large traction force. Moreover, the spatial distribution of RhoA differential activity at the basal plane strikingly mirrors this force cartography. We propose that RhoA controls the development of these fingers through mechanical cues: the leader cell drags the structure and the peripheral pluricellular acto-myosin cable prevents the initiation of new leader cells.

Promotion of Colorectal Cancer Invasion and Metastasis through Activation of NOTCH–DAB1–ABL–RHOGEF Protein TRIO

“…For example, RHO, rather than RAC, plays the key role in collective migration of epithelial cells ( 34 ), by which colorectal cancer very often invades into the stroma ( 3 ). Consistently, our present results show that TRIO Y2681F mutation reduces its RHOGEF activity ( Fig.…”

Epidermal Growth Factor Activates the Rho GTPase-activating Protein (GAP) Deleted in Liver Cancer 1 via Focal Adhesion Kinase and Protein Phosphatase 2A

“…For directional cell migration, it is important that the activity of Rho and RhoGAP is strictly regulated in a spatial and temporal manner. A recent study reiterates that spatial activation of RhoA is necessary for collective cell migration in response to mechanical cues that, in turn, alter the biochemical signaling (27). The significance of the phosphorylation followed by dephosphorylation of DLC1 can therefore be twofold.…”

Tuning Collective Cell Migration by Cell–Cell Junction Regulation

“…1D) (Friedl et al 1995;Alexander et al 2008;Montell et al 2012). Epithelial sheet movement is initiated by a row of leader cells coupled to follower cells by AJs containing E-or P-cadherin (Chapnick and Liu 2014;Plutoni et al 2016), and sheet displacement depends on coordinated traction force generation between leader and follower cells, which are distributed across cell -cell junctions by the actomyosin cytoskeleton (Brugues et al 2014;Reffay et al 2014;Bazellieres et al 2015). Moving clusters can be epithelial, such as the border cells moving along the boundaries of large nurse cells of the developing Drosphila ovary, or mesenchymal, such as moving neoplastic sheets in rhabodomyosarcoma explant culture (Friedl et al 1995).…”