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1. Feedback between mechanosensitive signaling and active forces governs endothelial junction integrity

   https://doi.org/10.1038/s41467-022-34701-y  

   McEvoy, Eoin; Sneh, Tal; Moeendarbary, Emad; Javanmardi, Yousef; Efimova, Nadia; Yang, Changsong; Marino-Bravante, Gloria E.; Chen, Xingyu; Escribano, Jorge; Spill, Fabian; et al (December 2022, Nature Communications)

   Abstract The formation and recovery of gaps in the vascular endothelium governs a wide range of physiological and pathological phenomena, from angiogenesis to tumor cell extravasation. However, the interplay between the mechanical and signaling processes that drive dynamic behavior in vascular endothelial cells is not well understood. In this study, we propose a chemo-mechanical model to investigate the regulation of endothelial junctions as dependent on the feedback between actomyosin contractility, VE-cadherin bond turnover, and actin polymerization, which mediate the forces exerted on the cell-cell interface. Simulations reveal that active cell tension can stabilize cadherin bonds, but excessive RhoA signaling can drive bond dissociation and junction failure. While actin polymerization aids gap closure, high levels of Rac1 can induce junction weakening. Combining the modeling framework with experiments, our model predicts the influence of pharmacological treatments on the junction state and identifies that a critical balance between RhoA and Rac1 expression is required to maintain junction stability. Our proposed framework can help guide the development of therapeutics that target the Rho family of GTPases and downstream active mechanical processes. 

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2. Steroid hormone signaling synchronizes cell migration machinery, adhesion and polarity to direct collective movement

   https://doi.org/10.1242/jcs.261164  

   Bhattacharya, Mallika; Starz-Gaiano, Michelle (March 2024, Journal of Cell Science)

   ABSTRACT Migratory cells – either individually or in cohesive groups – are critical for spatiotemporally regulated processes such as embryonic development and wound healing. Their dysregulation is the underlying cause of formidable health problems such as congenital abnormalities and metastatic cancers. Border cell behavior during Drosophila oogenesis provides an effective model to study temporally regulated, collective cell migration in vivo. Developmental timing in flies is primarily controlled by the steroid hormone ecdysone, which acts through a well-conserved, nuclear hormone receptor complex. Ecdysone signaling determines the timing of border cell migration, but the molecular mechanisms governing this remain obscure. We found that border cell clusters expressing a dominant-negative form of ecdysone receptor extended ineffective protrusions. Additionally, these clusters had aberrant spatial distributions of E-cadherin (E-cad), apical domain markers and activated myosin that did not overlap. Remediating their expression or activity individually in clusters mutant for ecdysone signaling did not restore proper migration. We propose that ecdysone signaling synchronizes the functional distribution of E-cadherin, atypical protein kinase C (aPKC), Discs large (Dlg1) and activated myosin post-transcriptionally to coordinate adhesion, polarity and contractility and temporally control collective cell migration. 

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3. Quantitative and Multiplexed Fluorescence Lifetime Imaging of Intercellular Tensile Forces

   https://doi.org/10.1002/anie.202103986  

   Keshri, Puspam; Zhao, Bin; Xie, Tianfa; Bagheri, Yousef; Chambers, James; Sun, Yubing; You, Mingxu (June 2021, Angewandte Chemie International Edition)

   Abstract Mechanical interactions between cells have been shown to play critical roles in regulating cell signaling and communications. However, the precise measurement of intercellular forces is still quite challenging, especially considering the complex environment at cell–cell junctions. In this study, we report a fluorescence lifetime‐based approach to image and quantify intercellular molecular tensions. Using this method, tensile forces among multiple ligand–receptor pairs can be measured simultaneously. We first validated our approach and developed lifetime measurement‐based DNA tension probes to image E‐cadherin‐mediated tension on epithelial cells. These probes were then further applied to quantify the correlations between E‐cadherin and N‐cadherin tensions during an epithelial–mesenchymal transition process. The modular design of these probes can potentially be used to study the mechanical features of various physiological and pathological processes. 

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4. Integrin β1 orchestrates the abnormal cell-matrix attachment and invasive behaviour of E-cadherin dysfunctional cells

   https://doi.org/10.1007/s10120-021-01239-9  

   Figueiredo, Joana; Ferreira, Rui M.; Xu, Han; Gonçalves, Margarida; Barros-Carvalho, André; Cravo, Janine; Maia, André F.; Carneiro, Patrícia; Figueiredo, Céu; Smith, Michael L.; et al (September 2021, Gastric Cancer)

   Abstract BackgroundTumour progression relies on the ability of cancer cells to penetrate and invade neighbouring tissues. E-cadherin loss is associated with increased cell invasion in gastric carcinoma, and germline mutations of the E-cadherin gene are causative of hereditary diffuse gastric cancer. Although E-cadherin dysfunction impacts cell–cell adhesion, cell dissemination also requires an imbalance of adhesion to the extracellular matrix (ECM). MethodsTo identify ECM components and receptors relevant for adhesion of E-cadherin dysfunctional cells, we implemented a novel ECM microarray platform coupled with molecular interaction networks. The functional role of putative candidates was determined by combining micropattern traction microscopy, protein modulation and in vivo approaches, as well as transcriptomic data of 262 gastric carcinoma samples, retrieved from the cancer genome atlas (TCGA). ResultsHere, we show that E-cadherin mutations induce an abnormal interplay of cells with specific components of the ECM, which encompasses increased traction forces and Integrin β1 activation. Integrin β1 synergizes with E-cadherin dysfunction, promoting cell scattering and invasion. The significance of the E-cadherin-Integrin β1 crosstalk was validated inDrosophilamodels and found to be consistent with evidence from human gastric carcinomas, where increased tumour grade and poor survival are associated with low E-cadherin and high Integrin β1 levels. ConclusionsIntegrin β1 is a key mediator of invasion in carcinomas with E-cadherin impairment and should be regarded as a biomarker of poor prognosis in gastric cancer. 

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5. Shear-induced damped oscillations in an epithelium depend on actomyosin contraction and E-cadherin cell adhesion

   https://doi.org/10.7554/eLife.39640  

   Sadeghipour, Ehsan; Garcia, Miguel A; Nelson, William James; Pruitt, Beth L (November 2018, eLife)

   Shear forces between cells occur during global changes in multicellular organization during morphogenesis and tissue growth, yet how cells sense shear forces and propagate a response across a tissue is unknown. We found that applying exogenous shear at the midline of an epithelium induced a local, short-term deformation near the shear plane, and a long-term collective oscillatory movement across the epithelium that spread from the shear-plane and gradually dampened. Inhibiting actomyosin contraction or E-cadherin trans-cell adhesion blocked oscillations, whereas stabilizing actin filaments prolonged oscillations. Combining these data with a model of epithelium mechanics supports a mechanism involving the generation of a shear-induced mechanical event at the shear plane which is then relayed across the epithelium by actomyosin contraction linked through E-cadherin. This causes an imbalance of forces in the epithelium, which is gradually dissipated through oscillatory cell movements and actin filament turnover to restore the force balance across the epithelium. 

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