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RESEARCH PRODUCT
Unjamming overcomes kinetic and proliferation arrest in terminally differentiated cells and promotes collective motility of carcinoma.
Fabio GiavazziEmanuele MartiniClaudio TripodoInes FerraraChiara MalinvernoGalina V. BeznoussenkoAndrea PalamidessiEmanuela FrittoliFlora AscioneElisabetta Ada Cavalcanti-adamRoberto CerbinoQingsen LiGiorgio ScitaMassimiliano GarrèDario ParazzoliPier Paolo Di FioreElisa BarbieriSalvatore CorallinoSara Sigismundsubject
EndosomeCellular differentiationmedia_common.quotation_subjectMotility02 engineering and technologySettore MED/08 - Anatomia Patologica010402 general chemistry01 natural sciencesExtracellular matrixCell MovementCell Line TumorHumansGeneral Materials ScienceSmall GTPaseEpidermal growth factor receptorInternalizationActinmedia_commonCell Proliferationrab5 GTP-Binding ProteinsMitogen-Activated Protein Kinase 1Mitogen-Activated Protein Kinase 3biologyChemistryMechanical EngineeringCell DifferentiationGeneral Chemistry021001 nanoscience & nanotechnologyCondensed Matter Physics0104 chemical sciencesCell biologyErbB ReceptorsKineticscarcinoma differentiated neoplastic cellsMechanics of Materialsbiology.protein0210 nano-technologydescription
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. A RAB5A-mediated, epidermal growth factor-dependent activation of endosomal ERK1/2 is identified as a key molecular route for a solid-to-liquid-like phase transition, sufficient to overcome kinetic and proliferation arrest in normal mammary epithelial assemblies and to promote collective invasion in breast carcinoma.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2019-11-01 | Nature materials |