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Girdin is a component of the lateral polarity protein network restricting cell dissemination

Abstract : Author summary Epithelia, composed of epithelial cells, delimit the frontier between the external environment and the inside of complex organisms. Therefore, epithelial cells cover the surface of the body (e.g. skin) and line internal cavities of organs (found in the intestine, liver, lungs, etc). An important function of epithelia is to selectively transport specific molecules to adjust the chemical composition of the different body compartments. This function relies on the asymmetric distribution of many cellular constituents, a structural organization referred to as epithelial polarity. The polarized architecture of epithelial cells is also required to maintain tissue homeostasis, as loss of epithelial polarity contributes to cancer progression. Here, we show that the protein GIRDIN is essential to maintain epithelial polarity in fruit flies and human cells. In addition, the absence of GIRDIN causes cell dissemination from tumor-like structures. This process is reminiscent to the formation of metastases (secondary tumors), which are the primary cause of mortality in cancer patients. It is thus not surprising that our data indicate that low GIRDIN levels are associated with a poor prognosis in some cancers. Overall, our study identifies GIRDIN as a potential target in cancer. Epithelial cell polarity defects support cancer progression. It is thus crucial to decipher the functional interactions within the polarity protein network. Here we show that Drosophila Girdin and its human ortholog (GIRDIN) sustain the function of crucial lateral polarity proteins by inhibiting the apical kinase aPKC. Loss of GIRDIN expression is also associated with overgrowth of disorganized cell cysts. Moreover, we observed cell dissemination from GIRDIN knockdown cysts and tumorspheres, thereby showing that GIRDIN supports the cohesion of multicellular epithelial structures. Consistent with these observations, alteration of GIRDIN expression is associated with poor overall survival in subtypes of breast and lung cancers. Overall, we discovered a core mechanism contributing to epithelial cell polarization from flies to humans. Our data also indicate that GIRDIN has the potential to impair the progression of epithelial cancers by preserving cell polarity and restricting cell dissemination.
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Contributor : Laurent Jonchère <>
Submitted on : Wednesday, May 6, 2020 - 10:50:06 AM
Last modification on : Thursday, June 18, 2020 - 12:32:06 PM

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Cornelia Biehler, Li-Ting Wang, Myriam Sevigny, Alexandra Jette, Clemence L. Gamblin, et al.. Girdin is a component of the lateral polarity protein network restricting cell dissemination. PLoS Genetics, Public Library of Science, 2020, 16 (3), pp.e1008674. ⟨10.1371/journal.pgen.1008674⟩. ⟨hal-02565098⟩



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