![]() For example, cell movements within tissues are required in some cases to maintain epithelial homeostasis ( Haigo and Bilder, 2011 Wang et al., 2013 Isabella and Horne-Badovinac, 2016), but in other cases, they are required to drive branching morphogenesis ( Ewald et al., 2008 Wang et al., 2017). ![]() But this model leaves unclear how the partial loss or gain of epithelial or mesenchymal traits, respectively, can orchestrate collective cell invasion ( O’Brien et al., 2004 Ewald et al., 2012). In these cases, a partial or transient EMT has been proffered to account for invasive behaviors exhibited by intact tissues ( O’Brien et al., 2002 Christiansen and Rajasekaran, 2006 Revenu and Gilmour, 2009 Friedl et al., 2012 Lambert et al., 2017). ![]() However, EMT does not adequately describe tissue shape changes when epithelial traits such as cell–cell adhesion are maintained ( Kowalski et al., 2003 Affolter et al., 2009 Shamir et al., 2014). EMT comprises a gene-regulatory program that simultaneously suppresses cells’ epithelial traits while activating mesenchymal traits, thereby stimulating invasion. A well-established framework describing the acquisition of invasive behaviors is the epithelial–mesenchymal transition (EMT Thiery et al., 2009). In both developmental and pathological contexts, shape changes undertaken by tissues rely on the coordination of cell motility and cell adhesions to neighboring cells and the ECM.Īn outstanding question is how tissues transition from compact structures dominated by cell–cell adhesions to invading cohorts of cells that interact extensively with their ECMs. Invasion by tumors is often accomplished by collective cell migration in a manner that frequently mimics development ( Gray et al., 2010 Friedl and Alexander, 2011). Malignant tissue can exhibit similar, if deregulated, shape changes during local invasion from the site of tumor formation ( Friedl et al., 2012). These cells subsequently lead cohorts of their neighbors out of their initial site, migrating collectively through the ECM to form extensively branched tubules ( O’Brien et al., 2002 Affolter et al., 2009). In many cases, branching morphogenesis is initiated when growth factors stimulate a few individual cells within the developing tissue to extend protrusions that adhere to the surrounding ECM. To form branched tubular networks, developing tissues such as mammalian vasculature or the Drosophila melanogaster trachea undergo extensive elongation and remodeling known as branching morphogenesis ( Lubarsky and Krasnow, 2003 Lecaudey and Gilmour, 2006 Wang et al., 2017). Tissue shape changes encompass multiple developmental and pathological processes. This work identifies Dia1 as an essential regulator of tissue shape changes through its role in stabilizing focal adhesions. Live imaging of actin, myosin, and collagen in control acini revealed adhesions that deformed individual collagen fibrils and generated large traction forces, whereas Dia1-depleted acini exhibited unstable adhesions with minimal collagen deformation and lower force generation. However, Dia1 was required to stabilize protrusions extending into the collagen matrix. Focusing on the role of the formin Dia1 in branching morphogenesis, we found that its depletion in MDCK cells does not alter planar cell motility either within the acinus or in two-dimensional scattering assays. ![]() Use of the broad-spectrum formin inhibitor SMIFH2 prevented the formation of migrating cell fronts in both cell types. We investigated cytoskeletal regulators during collective invasion by mouse tumor organoids and epithelial Madin–Darby canine kidney (MDCK) acini undergoing branching morphogenesis in collagen. Conserved mechanisms by which tissues initiate motility into their surroundings are not known. Developing tissues change shape and tumors initiate spreading through collective cell motility. ![]()
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