Unjamming overcomes kinetic and proliferation arrest in terminally differentiated cells and promotes collective motility of carcinoma.
Posted on: 15 November 2018
Preprint posted on 17 September 2018
Article now published in Nature Materials at http://dx.doi.org/10.1038/s41563-019-0425-1
Endocytic growth factor signaling induces proliferation and solid-to-liquid transitions in confluent epithelial tissues in 2D and 3D cell culture.
Selected by Tim Fessenden
Categories: biophysics, cancer biology, cell biology
Context
Granular materials (think of sand or grains of rice) can transition between a flowing, liquid-like state to a jammed state upon application or removal of an external stress. In the jammed state, constituent particles can no longer rearrange and the material behaves like a solid. While we find this a rather intuitive property of granular materials, a growing literature has proposed and characterized jamming and unjamming transitions in biological tissues.
Both mathematical models and experimental observations have built a strong case that tissues can exhibit liquid-like behaviors, such as cell rearrangements, or solid-like behaviors such as resistance to tension or compression1. Monolayers of epithelial cells can interchange between such states, driven for instance by changes in cell contractility or cell-cell adhesions2. Jamming thus offers a simple yet formalized physical framework to describe the material properties of tissues as an emergent property of actomyosin cytoskeletal dynamics. However, this framework is still poorly integrated with established biochemical signaling and cell motility behaviors in 2D and 3D culture.
Data
The present work offers a thorough analysis of the unjamming transition, including growth factor signaling, single-cell behaviors, and motility in 2D and 3D culture using MCF-10A, a human mammary epithelial cell line. Palamidessi and colleagues observe that within confluent monolayers, MCF-10A cells are normally immobile, corresponding to a jammed state, but become unjammed upon inducible expression of the endocytic receptor RAB5A. Previous work from this group showed potent effects of RAB5A on cell motility and invasion3. In more recent work, RAB5A was implicated in actomyosin dynamics driving unjamming in epithelial monolayers4. Here the authors use a suite of methods to demonstrate that RAB5A directly tunes growth factor signaling in endosomes, which leads to unjamming in MCF-10A monolayers through the actin regulator Wave-2.
Previous work analyzing jamming/unjamming transitions has relied on monolayers in 2D culture, where cells are immobile within jammed tissues. How are these behaviors manifested in spherical organoids? Curiously, inducible expression of RAB5A in mature organoids grown in Matrigel drives local rearrangement of neighboring cells, but in a context of rapid organoid rotation. Rotation has no immediate correlate for 2D monolayers but has been often observed in organoids, raising questions about the origin and significance of organoid rotation. When organoids were grown in collagen/matrigel mixtures, RAB5A expression induced multicellular invasion or budding into the matrix. Presumably this followed from rotation and rearrangements as observed in matrigel, in agreement with this reader’s published observations5. The authors conclude that RAB5A can induce first unjamming and invasion of initially immobile tissues, linking unjamming directly with phenotypes of malignant tissues in 2D and 3D.
Implications
By exploring this “reawakening” of cell motility in confluent tissues, Palamidessi and colleagues tie the perhaps overly broad phenomenon of unjamming to a set of well-studied motility and proliferative cell behaviors. This work invites the reader to rethink what cell motility means for epithelia and, just as important, provides an excellent example of how to study cell motility in both 2D and 3D contexts within one body of work.
References
- Mongera, A. et al. A fluid-to-solid jamming transition underlies vertebrate body axis elongation. Nature 561, 401–405 (2018).
- Bi, D., Lopez, J. H., Schwarz, J. M. & Manning, M. L. A density-independent rigidity transition in biological tissues. Nat. Phys. 11, 1074–1079 (2015).
- Frittoli, E. et al. A RAB5/RAB4 recycling circuitry induces a proteolytic invasive program and promotes tumor dissemination. J. Cell Biol. 206, 307–328 (2014).
- Malinverno, C. et al. Endocytic reawakening of motility in jammed epithelia. Nat. Mater. 16, 587–596 (2017).
- Fessenden, T. B. et al. Dia1-dependent adhesions are required by epithelial tissues to initiate invasion. J. Cell Biol. 217, 1485–1502 (2018).
doi: https://doi.org/10.1242/prelights.5571
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