Dataset Information

PD-LI promotes rear retraction during persistent cell migration by altering integrin β4 dynamics.

ABSTRACT: Although the immune checkpoint function of PD-L1 has dominated its study, we report that PD-L1 has an unanticipated intrinsic function in promoting the dynamics of persistent cell migration. PD-L1 concentrates at the rear of migrating carcinoma cells where it facilitates retraction, resulting in the formation of PD-L1-containing retraction fibers and migrasomes. PD-L1 promotes retraction by interacting with and localizing the β4 integrin to the rear enabling this integrin to stimulate contractility. This mechanism involves the ability of PD-L1 to maintain cell polarity and lower membrane tension at the cell rear compared with the leading edge that promotes the localized interaction of PD-L1 and the β4 integrin. This interaction enables the β4 integrin to engage the actin cytoskeleton and promote RhoA-mediated contractility. The implications of these findings with respect to cell-autonomous functions of PD-L1 and cancer biology are significant.

SUBMITTER: Wang M

PROVIDER: S-EPMC8965106 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Publications

PD-LI promotes rear retraction during persistent cell migration by altering integrin β4 dynamics.

Wang Mengdie M Xiong Choua C Mercurio Arthur M AM

The Journal of cell biology 20220328 5

Although the immune checkpoint function of PD-L1 has dominated its study, we report that PD-L1 has an unanticipated intrinsic function in promoting the dynamics of persistent cell migration. PD-L1 concentrates at the rear of migrating carcinoma cells where it facilitates retraction, resulting in the formation of PD-L1-containing retraction fibers and migrasomes. PD-L1 promotes retraction by interacting with and localizing the β4 integrin to the rear enabling this integrin to stimulate contractil ...[more]

PMID: 35344032

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Project description:Cell migration in 3D microenvironments is a complex process which depends on the coordinated activity of leading edge protrusive force and rear retraction in a push-pull mechanism. While the potentiation of protrusions has been widely studied, the precise signalling and mechanical events that lead to retraction of the cell rear are much less well understood, particularly in physiological 3D extra-cellular matrix (ECM). We previously discovered that rear retraction in fast moving cells is a highly dynamic process involving the precise spatiotemporal interplay of mechanosensing by caveolae and signalling through RhoA. To further interrogate the dynamics of rear retraction, we have adopted three distinct mathematical modelling approaches here based on (i) Boolean logic, (ii) deterministic kinetic ordinary differential equations (ODEs) and (iii) stochastic simulations. The aims of this multi-faceted approach are twofold: firstly to derive new biological insight into cell rear dynamics via generation of testable hypotheses and predictions; and secondly to compare and contrast the distinct modelling approaches when used to describe the same, relatively under-studied system. Overall, our modelling approaches complement each other, suggesting that such a multi-faceted approach is more informative than methods based on a single modelling technique to interrogate biological systems. Whilst Boolean logic was not able to fully recapitulate the complexity of rear retraction signalling, an ODE model could make plausible population level predictions. Stochastic simulations added a further level of complexity by accurately mimicking previous experimental findings and acting as a single cell simulator. Our approach highlighted the unanticipated role for CDK1 in rear retraction, a prediction we confirmed experimentally. Moreover, our models led to a novel prediction regarding the potential existence of a 'set point' in local stiffness gradients that promotes polarisation and rapid rear retraction.

Dataset Information

PD-LI promotes rear retraction during persistent cell migration by altering integrin β4 dynamics.

Publications

PD-LI promotes rear retraction during persistent cell migration by altering integrin β4 dynamics.

Similar Datasets

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