Kechagia, ZanettaSáez, PabloGómez González, ManuelCanales, BrendaViswanadha, SrivatsavaZamarbide, MartínAndreu, IonKoorman, ThijsBeedle, Amy E. M.Elosegui Artola, AlbertoDerksen, Patrick W. B.Trepat Guixer, XavierArroyo, MarinoRoca-Cusachs Soulere, Pere2023-10-092023-10-092023-09-141476-4660https://hdl.handle.net/2445/202705The mechanical properties of the extracellular matrix dictate tissue behaviour. In epithelial tissues, laminin is a very abundant extracellular matrix component and a key supporting element. Here we show that laminin hinders the mechanoresponses of breast epithelial cells by shielding the nucleus from mechanical deformation. Coating substrates with laminin-111-unlike fibronectin or collagen I-impairs cell response to substrate rigidity and YAP nuclear localization. Blocking the laminin-specific integrin β4 increases nuclear YAP ratios in a rigidity-dependent manner without affecting the cell forces or focal adhesions. By combining mechanical perturbations and mathematical modelling, we show that β4 integrins establish a mechanical linkage between the substrate and keratin cytoskeleton, which stiffens the network and shields the nucleus from actomyosin-mediated mechanical deformation. In turn, this affects the nuclear YAP mechanoresponses, chromatin methylation and cell invasion in three dimensions. Our results demonstrate a mechanism by which tissues can regulate their sensitivity to mechanical signals.© 2023. The Author(s).34 p.application/pdfengcc by (c) Kechagia, Zanetta et al., 2023http://creativecommons.org/licenses/by/3.0/es/Cèl·lules epitelialsGlicoproteïnesEpithelial cellsBiomecànicaGlycoproteinsBiomechanicsinfo:eu-repo/semantics/article2023-10-09info:eu-repo/semantics/openAccess660254937709930