Unjamming overcomes kinetic and proliferation arrest in terminally differentiated cells and promotes collective motility of carcinoma.

Andrea Palamidessi, Chiara Malinverno, Emanuela FRITTOLI, Salvatore Corallino, Elisa Barbieri, Sara Sigismund, Pier Paolo Di Fiore, Galina V Beznoussenko, Emanuele Martini, Massimiliano Garrè, Dario Parazzoli, Ines Ferrara, Claudio Tripodo, Fabio Giavazzi, Roberto Cerbino, Giorgio Scita

Preprint posted on 17 September 2018

Article now published in Nature Materials at

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


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.


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.


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.

Cell movements within control or RAB5A-expressing epithelial spheroids. Yellow arrows indicate movements of nuclei. Red arrow indicates the axis of rotation for each example. Plots at right indicate the time evolution of the velocity (top) and the rotational order parameter (bottom). Reproduced with permission from Figure 6B.



  1. Mongera, A. et al. A fluid-to-solid jamming transition underlies vertebrate body axis elongation. Nature 561, 401–405 (2018).
  2. 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).
  3. 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).
  4. Malinverno, C. et al. Endocytic reawakening of motility in jammed epithelia. Nat. Mater. 16, 587–596 (2017).
  5. Fessenden, T. B. et al. Dia1-dependent adhesions are required by epithelial tissues to initiate invasion. J. Cell Biol. 217, 1485–1502 (2018).

Tags: 3d, invasion, mcf-10a, motility, unjamming

Posted on: 15 November 2018


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Author's response

Giorgio Scita shared


Coherent angular rotation does not necessarily require unjamming, if we define unjamming as the ability to undergo neighbor exchange. Do you interpret those results as motility of a jammed tissue?

Author response:

I totally agree that circular angular rotation does not require unjamming, we have one set of measurements, however, where we looked at the overlap parameter Q […] Q is a function of time that decays from 1 to 0 according to the number of nuclei that have been substantially displaced from their original position, when observed in a reference frame co-moving with the whole spheroid. In RAB5A spheroids we observe a significantly faster decay indicative of local cell rearrangement (i.e. liquid motion). Thus we believe, that like in 2D monolayers, what RAB5A does is to cause long range correlated motion in the presence of local unjamming.

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