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Mechanisms of 3D cell migration

Abstract

Cell migration is essential for physiological processes as diverse as development, immune defence and wound healing. It is also a hallmark of cancer malignancy. Thousands of publications have elucidated detailed molecular and biophysical mechanisms of cultured cells migrating on flat, 2D substrates of glass and plastic. However, much less is known about how cells successfully navigate the complex 3D environments of living tissues. In these more complex, native environments, cells use multiple modes of migration, including mesenchymal, amoeboid, lobopodial and collective, and these are governed by the local extracellular microenvironment, specific modalities of Rho GTPase signalling and non-muscle myosin contractility. Migration through 3D environments is challenging because it requires the cell to squeeze through complex or dense extracellular structures. Doing so requires specific cellular adaptations to mechanical features of the extracellular matrix (ECM) or its remodelling. In addition, besides navigating through diverse ECM environments and overcoming extracellular barriers, cells often interact with neighbouring cells and tissues through physical and signalling interactions. Accordingly, cells need to call on an impressively wide diversity of mechanisms to meet these challenges. This Review examines how cells use both classical and novel mechanisms of locomotion as they traverse challenging 3D matrices and cellular environments. It focuses on principles rather than details of migratory mechanisms and draws comparisons between 1D, 2D and 3D migration.

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Fig. 1: ECM features that can regulate or modulate cell migration.
Fig. 2: The nucleus in 3D cell migration.
Fig. 3: Mesenchymal versus amoeboid migration.
Fig. 4: Strategies of collectively migrating cells.
Fig. 5: Mechanisms involved in collective cell migration.

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Acknowledgements

The authors apologize for not being able to cite many other excellent publications due to space limitations. Their laboratories are supported by the Intramural Research Program of the US National Institute of Dental and Craniofacial Research, the US National Institutes of Health, the European Research Council and the Austrian Science Fund (FWF).

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The authors contributed equally to all aspects of the article.

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Correspondence to Kenneth M. Yamada or Michael Sixt.

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Supplementary information

Supplementary Box 1

41580_2019_172_MOESM2_ESM.m4v

Supplementary Movie 1. A primary human fibroblast migrating in a 3D collagen matrix. In this overnight time-lapse movie, note how this mesenchymal cell generates multiple small lamellipodia at its leading edge, actively pulls and transiently locally compresses the collagen gel, and relatively passively drags forward the cell rear containing the nucleus. Movie generated by Marinilce Fagundes dos Santos and Kenneth Yamada.

41580_2019_172_MOESM3_ESM.m4v

Supplementary Movie 2. Amoeboid cell migration. This movie shows widefield imaging of a mature mouse dendritic cell migrating in a 3D collagen matrix of 1.3 mg/ml concentration. The movie sequence covers 23 min, and the nucleus is stained in blue. Movie generated by Jörg Renkawitz and Michael Sixt.

41580_2019_172_MOESM4_ESM.m4v

Supplementary Movie 3. Transient epithelial cell motility during organ branching morphogenesis. This time-lapse movie shows dynamic movements of cells of a mouse embryonic salivary gland (embryonic day 13) by two-photon microscopy. The cells were from a transgenic mouse expressing both histone-EGFP (shown in magenta) and membrane-tdTomato (green). At this stage, the rapidly developing epithelium (bottom left) is surrounded by loosely condensed mesenchyme. Images were acquired at 5-minute intervals. Movie generated by Shaohe Wang.

Glossary

Neural crest cells

Embryonic cells derived from the border of the neural plate and non-neural ectoderm that disperse by migration. They contribute to many of the structures of the face and skull, as well as contribute to forming the peripheral nervous system, sensory ganglia, melanocytes and other tissues.

Leading edge

The front end of a migrating cell. Polarized cells generally extend protrusions forward in the direction of migration at this end.

Lamellipodia

Thin, sheet-like protrusions at the leading edge of cells that are generated by actin polymerization and are supported by a branched actin meshwork. They extend the edge of the cell during cell migration.

Focal adhesion

A subcellular structure mediating cell adhesion to extracellular matrix that can transmit force to and from cells. Focal adhesions can also serve as hubs for signalling molecules to generate or modulate signal transduction.

Blebs

Microscopic, rounded bulges in the plasma membrane containing small amounts of cytoplasm. Blebs arise from a local disruption of plasma membrane–actin cortex interaction, so a region of plasma membrane lacking associated cortical actin bulges outward due to intracellular actomyosin-driven hydrostatic pressure. Amoeboid migration is often associated with blebbing.

Lobopodia

Blunt cellular protrusions at the front of migrating cells that extend by protrusive outward deformation of the plasma membrane due to polarized intracellular hydrostatic pressure.

Clutch molecules

Intracellular proteins comprising the molecular clutch mechanism of focal adhesions, which transmits force between rearward-moving (retrograde) actin flow and the cell surface. The molecules in this clutch engage and slip dynamically to link the actively translocating actin cytoskeleton to cell motility.

Basement membranes

Thin, sheet-like extracellular matrix structures that underlie epithelia and often separate them from connective tissue.

Filopodia

Slender, finger-like microscopic plasma membrane protrusions containing bundles of actin filaments. Cells can use filopodia to probe the local microenvironment and to provide local sites of attachment at their tips.

Invadopodia

Slender, finger-like microscopic protrusions enriched in protease activity that are implicated in cancer invasion into extracellular matrix.

Cell traction

The application of force by a cell to a substrate.

Elastic energy

Mechanical energy stored in a stretched material.

Polymorphonuclear leukocytes

A subset of white blood cells also known as neutrophil granulocytes. They are characterized by the presence of enzyme-containing granules and lobed nuclei of various shapes.

Dendritic cells

Cells of the mammalian immune system that process antigens and present them on their cell surface to T lymphocytes for initiation of an immunological response. They can be highly migratory.

Arp2/3 complex

A protein complex composed of seven subunits that initiates actin polymerization to form branched actin networks. This complex is essential for the formation of lamellipodia.

Stress fibres

Bundles of F-actin with non-muscle myosin II and actin-crosslinking proteins that insert themselves into cellular adhesions to the extracellular matrix or other substrates. Stress fibres are contractile and can generate force on adhesions through non-muscle actomyosin contractility.

Friction

Resistance to movement of a cellular contact site as the cell rubs or pushes against a local extracellular matrix structure such as a fibril or surface.

Glycocalyx

The carbohydrate-rich molecular layer at the outer surface of cells comprising glycoproteins, glycolipids and glycosaminoglycans.

Paxillin

An adaptor protein of the cytoskeleton that is a cell adhesion and signalling molecule that binds and interconnects vinculin and multiple other proteins.

Vinculin

An adaptor protein of the cytoskeleton that can link integrin-associated molecules such as talin to F-actin in macromolecular cell adhesion complexes.

Epithelial–mesenchymal transition

(EMT). A biological process involving loss of epithelial cell properties and a gain of a primitive fibroblast-like phenotype, including enhanced migration.

Convergent extension

A developmental process in which a tissue extends in one direction by convergence and intercalation of cells from its lateral sides.

Hypoxia-inducible factor 1

A regulatory protein complex that becomes stabilized against degradation under reduced oxygen conditions; it induces the expression of several genes to promote survival during hypoxia.

Cancer-associated fibroblasts

Activated fibroblasts associated with tumours and tumour stroma that can enhance cancer-related processes by secreting cytokines or remodelling the extracellular matrix.

Presomitic mesoderm

Mesodermal cells that become organized into somites during embryonic development.

Branching morphogenesis

Embryonic process by which multiple organs generate tree-like architectures to expand their surface area.

Border cells

A cluster of migratory ovarian cells during Drosophila melanogaster development.

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Yamada, K.M., Sixt, M. Mechanisms of 3D cell migration. Nat Rev Mol Cell Biol 20, 738–752 (2019). https://doi.org/10.1038/s41580-019-0172-9

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