Mammary collective cell migration involves transient loss of epithelial features and individual cell migration within the epithelium

Department of Anatomy, University of California-San Francisco, San Francisco, CA 94143, USA.
Journal of Cell Science (Impact Factor: 5.43). 02/2012; 125(Pt 11):2638-54. DOI: 10.1242/jcs.096875
Source: PubMed


Normal mammary morphogenesis involves transitions between simple and multilayered epithelial organizations. We used electron microscopy and molecular markers to determine whether intercellular junctions and apico-basal polarity were maintained in the multilayered epithelium. We found that multilayered elongating ducts had polarized apical and basal tissue surfaces both in three-dimensional culture and in vivo. However, individual cells were only polarized on surfaces in contact with the lumen or extracellular matrix. The basolateral marker scribble and the apical marker atypical protein kinase C zeta localized to all interior cell membranes, whereas PAR3 displayed a cytoplasmic localization, suggesting that the apico-basal polarity was incomplete. Despite membrane localization of E-cadherin and β-catenin, we did not observe a defined zonula adherens connecting interior cells. Instead, interior cells were connected through desmosomes and exhibited complex interdigitating membrane protrusions. Single-cell labeling revealed that individual cells were both protrusive and migratory within the epithelial multilayer. Inhibition of Rho kinase (ROCK) further reduced intercellular adhesion on apical and lateral surfaces but did not disrupt basal tissue organization. Following morphogenesis, segregated membrane domains were re-established and junctional complexes re-formed. We observed similar epithelial organization during mammary morphogenesis in organotypic culture and in vivo. We conclude that mammary epithelial morphogenesis involves a reversible, spatially limited, reduction in polarity and intercellular junctions and active individualistic cell migration. Our data suggest that reductions in polarity and adhesion during breast cancer progression might reflect partial recapitulation of a normal developmental program.

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    • "Interestingly, this process resembles normal events during mammary branching morphogenesis, when ducts become multilayered at the leading tips of growing ducts. The inner cells within the multilayered epithelium transiently lose apical–basal polarity, with aPKC colocalizing with basolateral proteins β-catenin and Scrib, and Par3 becoming delocalized to the cytoplasm.44 "
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    ABSTRACT: Breast cancer is a heterogeneous group of diseases that frequently exhibits loss of growth control, and disrupted tissue organization and differentiation. Several recent studies indicate that apical-basal polarity provides a tumor-suppressive function, and that disrupting polarity proteins affects many stages of breast cancer progression from initiation through metastasis. In this review we highlight some of the recent advances in our understanding of the molecular mechanisms by which loss of apical-basal polarity deregulates apoptosis, proliferation, and promotes invasion and metastasis in breast cancer.
    Breast Cancer: Targets and Therapy 01/2014; 6:15-27. DOI:10.2147/BCTT.S43764
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    • "Movie S1, which is available online). Although previous studies have used adenovirus infection of individual cells to track movements of salivary and mammary gland cells during this process of branching morphogenesis (Larsen et al., 2006; Ewald et al., 2012), it is not clear whether this approach might target only certain types of cells or could have subtle effects on cell migration. Consequently, we chose to use a transgenic mouse approach in which a fluorescent probe is expressed in all cells of an animal that undergoes normal embryonic development and organ morphogenesis . "
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    ABSTRACT: Background: Epithelial cells of developing embryonic organs, such as salivary glands, can display substantial motility during branching morphogenesis. Their dynamic movements and molecules involved in their migration are not fully characterized. Results: We generated transgenic mice expressing photo-convertible KikGR and tracked the movements of individual cells highlighted by red fluorescence in different regions of developing salivary glands. Motility was highest for outer bud epithelial cells adjacent to the basement membrane, lower in inner bud cells, and lowest in duct cells. The highly motile outer cells contacting the basement membrane were pleomorphic, whereas inner cells were rounded. Peripheral cell motility was disrupted by antibodies inhibiting α6+β1 integrins and the nonmuscle myosin II inhibitor blebbistatin. Inner bud cell migration was unaffected by these inhibitors, but their rate of migration was stimulated by inhibiting E-cadherin. Conclusions: Cell motility in developing salivary glands was highest in cells in contact with the basement membrane. The basement membrane-associated motility of these outer bud cells depended on integrins and myosin II, but not E-cadherin. In contrast, motility of inner bud cells was restrained by E-cadherin. These findings identify the importance of integrin-dependent basement membrane association for the morphology, tissue organization, and lateral motility of morphogenetic epithelial cells.
    Developmental Dynamics 09/2013; 242(9). DOI:10.1002/dvdy.24000 · 2.38 Impact Factor
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    ABSTRACT: Most invasive solid tumours display predominantly collective invasion, in which groups of cells invade the peritumoral stroma while maintaining cell-cell contacts. As the concepts and experimental models for functional analysis of collective cancer cell invasion are rapidly developing, we propose a framework for addressing potential mechanisms, experimental strategies and technical challenges to study this process.
    Nature Cell Biology 08/2012; 14(8):777-83. DOI:10.1038/ncb2548 · 19.68 Impact Factor
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