Dataset Information

Membrane Tension Orchestrates Rear Retraction in Matrix-Directed Cell Migration.

ABSTRACT: In development, wound healing, and cancer metastasis, vertebrate cells move through 3D interstitial matrix, responding to chemical and physical guidance cues. Protrusion at the cell front has been extensively studied, but the retraction phase of the migration cycle is not well understood. Here, we show that fast-moving cells guided by matrix cues establish positive feedback control of rear retraction by sensing membrane tension. We reveal a mechanism of rear retraction in 3D matrix and durotaxis controlled by caveolae, which form in response to low membrane tension at the cell rear. Caveolae activate RhoA-ROCK1/PKN2 signaling via the RhoA guanidine nucleotide exchange factor (GEF) Ect2 to control local F-actin organization and contractility in this subcellular region and promote translocation of the cell rear. A positive feedback loop between cytoskeletal signaling and membrane tension leads to rapid retraction to complete the migration cycle in fast-moving cells, providing directional memory to drive persistent cell migration in complex matrices.

SUBMITTER: Hetmanski JHR

PROVIDER: S-EPMC6863396 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Publications

Membrane Tension Orchestrates Rear Retraction in Matrix-Directed Cell Migration.

Hetmanski Joseph H R JHR de Belly Henry H Busnelli Ignacio I Waring Thomas T Nair Roshna V RV Sokleva Vanesa V Dobre Oana O Cameron Angus A Gauthier Nils N Lamaze Christophe C Swift Joe J Del Campo Aránzazu A Starborg Tobias T Zech Tobias T Goetz Jacky G JG Paluch Ewa K EK Schwartz Jean-Marc JM Caswell Patrick T PT

Developmental cell 20191010 4

In development, wound healing, and cancer metastasis, vertebrate cells move through 3D interstitial matrix, responding to chemical and physical guidance cues. Protrusion at the cell front has been extensively studied, but the retraction phase of the migration cycle is not well understood. Here, we show that fast-moving cells guided by matrix cues establish positive feedback control of rear retraction by sensing membrane tension. We reveal a mechanism of rear retraction in 3D matrix and durotaxis ...[more]

PMID: 31607653

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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

Membrane Tension Orchestrates Rear Retraction in Matrix-Directed Cell Migration.

Publications

Membrane Tension Orchestrates Rear Retraction in Matrix-Directed Cell Migration.

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