Contact inhibition of locomotion in vivo controls neural crest directional migration

Carmona‐Fontaine, Carlos; Matthews, Helen K.; Kuriyama, Sei; Moreno, Mauricio; Dunn, Graham; Parsons, Maddy; Stern, Claudio D.; Mayor, Roberto

doi:10.1038/nature07441

Cited by 543 publications

(776 citation statements)

References 28 publications

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“…In the 2D wound-healing experiment, the cancer cells appeared to expand outward into the soft matrix, basically as a free gas of cells, which is consistent with the idea that cancer cells do not obey contact inhibition (34,48,49). However, for the 3D metastatic invading front, it would appear that there are correlations between the invading cells on the front because it remains a fairly tightly focused front and does not disperse.…”

Section: Discussionsupporting

confidence: 68%

Minimization of thermodynamic costs in cancer cell invasion

Liu

Duclos

Sun³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Metastasis, the truly lethal aspect of cancer, occurs when metastatic cancer cells in a tumor break through the basement membrane and penetrate the extracellular matrix. We show that MDA-MB-231 metastatic breast cancer cells cooperatively invade a 3D collagen matrix while following a glucose gradient. The invasion front of the cells is a dynamic one, with different cells assuming the lead on a time scale of 70 h. The front cell leadership is dynamic presumably because of metabolic costs associated with a long-range strain field that precedes the invading cell front, which we have imaged using confocal imaging and marker beads imbedded in the collagen matrix. We suggest this could be a quantitative assay for an invasive phenotype tracking a glucose gradient and show that the invading cells act in a cooperative manner by exchanging leaders in the invading front.T umor metastasis is obviously of enormous clinical importance.A fundamental physiologic and clinical difference between benign and malignant tumor cells is that the former are usually neither invasive nor fatal. It is currently difficult to predict the probability of metastasis from the morphological or phenotypic properties of tumor cells observed within a primary cancer. Invasive tumor growth, at both primary and secondary sites, requires tumor cells to break through the stromal tissue barrier, evade the immune system, and coordinate signaling among tumor and mesenchymal cells to promote formation of tissue infrastructure, such as angiogenesis, to maintain tumor viability in its newly invaded space (1). We test two hypotheses: (i) The extreme thermodynamic costs of the oxidative Warburg cycle used by cancer cells forces them to follow glucose gradients; and (ii) minimization of the thermodynamic costs can be achieved by collective invasion strategies.Invading cells are subject to significant potential fitness costs that may be minimized by collective behavior. Metastatic tumor cells that leave the primary tumor have to break through the stromal tissue barrier, evade the immune system, and coordinate with other local cells during angiogenesis to finally set up a viable remote tumor. It has been estimated that less than 1% of the primary tumor cells are able to finish the metastasis cycle (2), and yet they contribute to more than 90% of the cancer-related deaths (3). Although the molecular details are still unclear, it is significant that the malignant transition is accompanied by a change in the metabolism pathway from the mitochondrial oxidation of pyruvate in mitochondria (an aerobic process) to the far less energy-efficient and ancient anaerobic pathway of glycolysis followed by lactic acid fermentation in the cytosol (4), known as the Warburg cycle (5).Most, if not all, metastatic cancer cells use the Warburg cycle, which is a far less efficient metabolism in terms of ATP production (6), consuming glucose (glycolysis) rather than using the usual oxidative Krebs phosphorylation cycle, although, thermodynamically, the process is efficient in the storage...

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Section: Discussionsupporting

confidence: 68%

Minimization of thermodynamic costs in cancer cell invasion

Liu

Duclos

Sun³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Y-27632 inhibits homotypic CIL in NC cells [3]. Transient RhoA activation may be required for both types of CIL while constitutive activation interferes with CIL.…”

Section: Discussionmentioning

confidence: 93%

“…The Wnt Planar Cell Polarity (PCP or non-canomical) pathway is required for homotypic CIL between migrating NC cells [3]. Elements of the pathway become co-localized at the site of cell contact.…”

Section: Introductionmentioning

confidence: 99%

The effects of modifying RhoA and Rac1 activities on heterotypic contact inhibition of locomotion

Anear

Parish

2012

FEBS Letters

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a b s t r a c tContact inhibition of locomotion (CIL) occurs when a cell ceases moving in the same direction following contact with another cell. Homotypic and heterotypic CIL occur between cells of the same and different types, respectively. Using Abercrombie's confronted explants assay we studied the effect of changing Rac1 or RhoA activities on heterotypic CIL between NIH3T3 and chicken heart fibroblasts. Both dominant active (L61) and dominant negative (N17) Rac1 expressed in NIH3T3 cells resulted in loss of heterotypic CIL. N17Rac1 expression caused RhoA activation. Increasing RhoA activity directly (V14RhoA) or indirectly (downregulation of N-cadherin or p120-catenin) also resulted in loss of CIL. High RhoA activity has been associated with tumour invasion and our results are consistent with loss of heterotypic CIL playing a role.

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“…Nevertheless, some mesenchymal cells can also migrate collectively as a consequence of CIL (6,13,23) or of increased cell-cell adhesion (46). Therefore, these specific phenotypes might also correspond to the active polar liquid state.…”

Section: Discussion and Perspectivesmentioning

confidence: 99%

“…This interaction has been shown to be crucial in determining the collective behavior of cell groups in several contexts (22). For example, CIL guides the directional migration of neural crest cells (23) and also ensures the correct dispersion of Cajal-Retzius cells in the cerebral cortex (24) or of hemocytes in the embryo (25).…”

mentioning

confidence: 99%

Emergent structures and dynamics of cell colonies by contact inhibition of locomotion

Smeets

Alert

Pešek

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Cells in tissues can organize into a broad spectrum of structures according to their function. Drastic changes of organization, such as epithelial-mesenchymal transitions or the formation of spheroidal aggregates, are often associated either to tissue morphogenesis or to cancer progression. Here, we study the organization of cell colonies by means of simulations of self-propelled particles with generic cell-like interactions. The interplay between cell softness, cell-cell adhesion, and contact inhibition of locomotion (CIL) yields structures and collective dynamics observed in several existing tissue phenotypes. These include regular distributions of cells, dynamic cell clusters, gel-like networks, collectively migrating monolayers, and 3D aggregates. We give analytical predictions for transitions between noncohesive, cohesive, and 3D cell arrangements. We explicitly show how CIL yields an effective repulsion that promotes cell dispersal, thereby hindering the formation of cohesive tissues. Yet, in continuous monolayers, CIL leads to collective cell motion, ensures tensile intercellular stresses, and opposes cell extrusion. Thus, our work highlights the prominent role of CIL in determining the emergent structures and dynamics of cell colonies.self-propelled particles | cell-cell adhesion | contact inhibition of locomotion | cell monolayers | collective motion C ell colonies exhibit a broad range of phenotypes. In terms of structure, collections of cells can arrange into distributions of single cells, assemble into continuous monolayers or multilayered tissues, or even form 3D agglomerates. In terms of dynamics, cell motility may simply be absent or produce random, directed, or collective migration of cells. Transitions between these states of tissue organization are characteristic of morphogenetic events and are also central to tumor formation and dispersal (1-4). Therefore, a physical understanding of the collective behavior of cell colonies will shed light on the regulation of many multicellular processes involved in development and disease.However, a complete physical picture of multicellular organization is not yet available, partly due to the challenge of modeling the complex interactions between cells. Here, we address this problem by means of large-scale simulations of self-propelled particles (SPP) endowed with interactions capturing generic cellular behaviors. Models of SPP with aligning interactions have been used to investigate collective cell motions in tissue monolayers (5-18). We extend this approach to unveil how the different structures and collective dynamics of cell colonies emerge from cell-cell interactions.In addition to an excluded-volume repulsion, cells generally feature a short-range attraction as a consequence of their active cortical contractility transmitted through cell-cell junctions. With no additional interactions, this attraction would typically lead to cohesive tissues. However, not all cell types form cohesive tissues. Whereas epithelial cells tend to form continuous monolayers...

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Contact inhibition of locomotion in vivo controls neural crest directional migration

Cited by 543 publications

References 28 publications

Minimization of thermodynamic costs in cancer cell invasion

Minimization of thermodynamic costs in cancer cell invasion

The effects of modifying RhoA and Rac1 activities on heterotypic contact inhibition of locomotion

Emergent structures and dynamics of cell colonies by contact inhibition of locomotion

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