Mechanical Stabilization of the Glandular Acinus by Linker of Nucleoskeleton and Cytoskeleton Complex

• Published in: Current biology 2019-09, Vol.29 (17), p.2826-2839.e4
• Main Authors: Zhang, Qiao, Narayanan, Vani, Mui, Keeley L., O’Bryan, Christopher S., Anderson, Ruthellen H., KC, Birendra, Cabe, Jolene I., Denis, Kevin B., Antoku, Susumu, Roux, Kyle J., Dickinson, Richard B., Angelini, Thomas E., Gundersen, Gregg G., Conway, Daniel E., Lele, Tanmay P.
• Format: Article
• Language: English
• Subjects: 3D culture; Acinar Cells - physiology; acinar development; actomyosin contractility; Animals; Biomechanical Phenomena; breast cancer; Cytoskeleton - physiology; Dogs; fluctuations; Humans; LINC complex; lumenal filling; Madin Darby Canine Kidney Cells; Nuclear Matrix - physiology; nuclear mechanics; nucleus; tissue mechanics
• ISSN: 0960-9822; 1879-0445
• DOI: 10.1016/j.cub.2019.07.021

The nucleoskeleton and cytoskeleton are important protein networks that govern cellular behavior and are connected together by the linker of nucleoskeleton and cytoskeleton (LINC) complex. Mutations in LINC complex components may be relevant to cancer, but how cell-level changes might translate into tissue-level malignancy is unclear. We used glandular epithelial cells in a three-dimensional culture model to investigate the effect of perturbations of the LINC complex on higher order cellular architecture. We show that inducible LINC complex disruption in human mammary epithelial MCF-10A cells and canine kidney epithelial MDCK II cells mechanically destabilizes the acinus. Lumenal collapse occurs because the acinus is unstable to increased mechanical tension that is caused by upregulation of Rho-kinase-dependent non-muscle myosin II motor activity. These findings provide a potential mechanistic explanation for how disruption of LINC complex may contribute to a loss of tissue structure in glandular epithelia. •The LINC complex is required for normal development of epithelial acini with lumens•LINC complex disruption increases myosin regulatory light chain phosphorylation•Increased myosin activity causes collapse of the dynamically fluctuating acinus•The LINC complex mechanically stabilizes the epithelial acinus Zhang et al. describe a functional role for the LINC complex, which links the nucleus to the cytoskeleton, in acinar development. Disrupting the LINC complex causes the development of acini with occluded lumens and upregulates myosin II regulatory light chain phosphorylation. This mechanically destabilizes the dynamically fluctuating acinus.