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

Nature Materials volume 18, pages 1252–1263 (2019)Cite this article

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A Publisher Correction to this article was published on 27 September 2022

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Abstract

During wound repair, branching morphogenesis and carcinoma dissemination, cellular rearrangements are fostered by a solid-to-liquid transition, known as unjamming. The biomolecular machinery behind unjamming and its pathophysiological relevance remain, however, unclear. Here, we study unjamming in a variety of normal and tumorigenic epithelial two-dimensional (2D) and 3D collectives. Biologically, the increased level of the small GTPase RAB5A sparks unjamming by promoting non-clathrin-dependent internalization of epidermal growth factor receptor that leads to hyperactivation of the kinase ERK1/2 and phosphorylation of the actin nucleator WAVE2. This cascade triggers collective motility effects with striking biophysical consequences. Specifically, unjamming in tumour spheroids is accompanied by persistent and coordinated rotations that progressively remodel the extracellular matrix, while simultaneously fluidizing cells at the periphery. This concurrent action results in collective invasion, supporting the concept that the endo-ERK1/2 pathway is a physicochemical switch to initiate collective invasion and dissemination of otherwise jammed carcinoma.

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Fig. 1: Endocytic reawakening of motility is dependent on EGFR activation.
Fig. 2: RAB5A increases non-clathrin internalization of EGFR.
Fig. 3: RAB5A endosomal ERK1/2 activity is required for flocking locomotion.
Fig. 4: RAB5A overcomes kinetic and proliferation arrest in terminally differentiated acini.
Fig. 5: RAB5A promotes the emergence of coordinated angular rotation in cancer spheroids.
Fig. 6: RAB5A promotes collective invasion in tumour spheroids and tumour slices.

Data availability

The authors declare that all data supporting the findings of this study are available within the paper and its supplementary Information files and from the corresponding authors upon reasonable request.

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The codes used for the analysis are all indicated in the Methods.

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Acknowledgements

This work has been supported by: the Associazione Italiana per la Ricerca sul Cancro (AIRC) to G.S. (IG#18621), P.P.D.F (IG#18988 and MCO 10.000), and F.G. (MFAG#22083); the Italian Ministry of University and Scientific Research (MIUR) to P.P.D.F. and G.S. (PRIN: PROGETTI DI RICERCA DI RILEVANTE INTERESSE NAZIONALE – Bando 2017#2017HWTP2K); the Italian Ministry of Health (RF-2013-02358446) to G.S. Regione Lombardia and CARIPLO foundation (Project 2016-0998) to R.C.; Worldwide Cancer Research (WCR#16-1245) to S.S. C.M. and F.G. are partially supported by fellowships from the University of Milan, E.B. from the FIRC-AIRC. We thank J. Christian (Max Planck Institute for Medical Research, Heidelberg, Germany) for help with fluorescent beads.

Author information

Author notes

  1. These authors contributed equally: Andrea Palamidessi, Chiara Malinverno, Emanuela Frittoli.

Authors and Affiliations

  1. IFOM, the FIRC Institute of Molecular Oncology, Milan, Italy

    Andrea Palamidessi, Chiara Malinverno, Emanuela Frittoli, Salvatore Corallino, Galina V. Beznoussenko, Emanuele Martini, Massimiliano Garre, Claudio Tripodo, Flora Ascione, Qingsen Li, Dario Parazzoli & Giorgio Scita

  2. University of Milan, Department of Oncology and Hemato-Oncology, Milan, Italy

    Chiara Malinverno, Sara Sigismund, Pier Paolo Di Fiore & Giorgio Scita

  3. Istituto Europeo di Oncologia IRCCS, Milan, Italy

    Elisa Barbieri, Sara Sigismund & Pier Paolo Di Fiore

  4. Department of Health Sciences, Human Pathology Section, University of Palermo School of Medicine, Palermo, Italy

    Ines Ferrara & Claudio Tripodo

  5. Max Planck Institute for Medical Research, Heidelberg, Germany

    Elisabetta A. Cavalcanti-Adam

  6. University of Milan, Department of Medical Biotechnology and Translational Medicine, Segrate, Italy

    Fabio Giavazzi & Roberto Cerbino

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  1. Andrea Palamidessi
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Contributions

A.P., C.M. and E.F. designed and performed all the experiments and edited the manuscript. S.C. aided in generating cell lines and in the analysis of immunofluorescence and kinematic studies. E.B., S.S. and P.P.F.D. conceived the internalization assays and interpreted the trafficking results. G.V.B. performed EM studies. E.M., M.G. and D.P. aided in all the imaging acquisition, FRET and PIV analysis. C.T aided in the analysis of RAB5A expression in breast cancer. Q.L. and F.A. performed and analysed the AFM measurements. F.G. and R.C. analysed all the kinematic data, developed the tools for 3D motility and mechanical analysis, edited the manuscript and conceived part of the study together with C.M. E.A.C.-A helped in setting up the fluorescent bead assay. G.S. conceived the whole study, wrote the manuscript and supervised all the work. C.M., F.G., R.C. and G.S. are all equally responsible for this work.

Corresponding authors

Correspondence to Chiara Malinverno, Fabio Giavazzi, Roberto Cerbino or Giorgio Scita.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–12, Supplementary Tables 1–4, Supplementary Video Legends 1–29, Supplementary Discussion and Supplementary references 1–19

Reporting Summary

Supplementary Video 1

RAB5A reawakening of collective motion in jammed epithelial monolayers depends on EGF

Supplementary Video 2

RAB5A reawakening of collective motion in jammed epithelial monolayers depends on EGFR

Supplementary Video 3

EGF-dependence of RAB5A flocking motility in EGFP-H2B-jammed epithelia monolayers

Supplementary Video 4

PIV analysis of EGF and EGFR-dependent endocytic unjamming

Supplementary Video5

RAB5A flocking motion in jammed epithelia is reduced by silencing Dynamin 2

Supplementary Video 6

RAB5A flocking motion in jammed epithelia is reduced by silencing RTN3, but not RTN4

Supplementary Video 7

RAB5A, but neither RAB5B nor RAB5C induces flocking motion in jammed epithelia

Supplementary Video 8

Flocking motion is abrogated by treatment with inhibitors of the MAPK/ERK1/2 pathway

Supplementary Video 9

Flocking motion is abrogated by treatment with Dynasore

Supplementary Video 10

MEK-DD is not sufficient to reawaken collective motion in jammed MCF10A monolayers

Supplementary Video 11

RAB5A-induced cryptic lamellipodia is compromised by treatment with MEK1/2 inhibitor

Supplementary Video 12

RAB5A-induced cryptic lamellipodia are inhibited by silencing the WAVE complex

Supplementary Video 13

RAB5A reawakening of collective motion in jammed epithelia is impaired by silencing NAP1

Supplementary Video 14

Silencing of NAP1 or WAVE2 affects RAB5A-induced wound closure in epithelial monolayers

Supplementary Video 15

Acini kinematic motility assay

Supplementary Video 16

PIV analysis on acini motility

Supplementary Video 17

RAB5A-mediated unjamming in MCF10A acini is trafficking-, EGFR- and ERK1/2-dependent

Supplementary Video 18

RAB5A-induced angular motion of MCF10A is independent of cell proliferation

Supplementary Video 19

RAB5A overcomes kinetic arrest of differentiated MCF10A acini

Supplementary Video 20

RAB5A reawakens collective motion in jammed MCF10.DCIS.com carcinoma cells

Supplementary Video 21

RAB5A promotes wound closure and flocking motion

Supplementary Video 22

RAB5A-mediated unjamming induces coordinated angular rotation in breast cancer spheroids

Supplementary Video 23

3D DVA of a RAB5A rotating spheroid after removal of the global rotation

Supplementary Video 24

RAB5A-flocking in spheroids is trafficking-, EGFR-, ERK1/2- and ARP2/3-dependent

Supplementary Video 25

RAB5A-mediated 3D unjamming promotes collective invasion in tumour spheroids

Supplementary Video 26

RAB5A spheroids exert larger stresses on surrounding ECM

Supplementary Video 27

Instantaneous velocity and stress maps of control and RAB5A-expressing spheroids.

Supplementary Video 28

RAB5A-mediated flocking promotes collective invasion in ex vivo DCIS tumour slices

Supplementary Video 29

PIV analysis on ex vivo DCIS tumour slice motility

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Palamidessi, A., Malinverno, C., Frittoli, E. et al. Unjamming overcomes kinetic and proliferation arrest in terminally differentiated cells and promotes collective motility of carcinoma. Nat. Mater. 18, 1252–1263 (2019). https://doi.org/10.1038/s41563-019-0425-1

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