title: Invadopodia biogenesis is regulated by caveolin-mediated modulation of membrane cholesterol levels.
abstract: Invadopodia are proteolytically active protrusions formed by invasive tumoural cells when grown on an extracellular matrix (ECM) substratum. Clearly, invadopodia are specialized membrane domains acting as sites of signal transduction and polarized delivery of components required for focalized ECM degradation. For these reasons, invadopodia are a model to study focal ECM degradation by tumour cells. We investigated the features of invadopodia membrane domains and how altering their composition would affect invadopodia biogenesis and function. This was achieved through multiple approaches including manipulation of the levels of cholesterol and other lipids at the plasma membrane, alteration of cholesterol trafficking by acting on caveolin 1 expression and phosphorylation. We show that cholesterol depletion impairs invadopodia formation and persistence, and that invadopodia themselves are cholesterol-rich membranes. Furthermore, the inhibition of invadopodia formation and ECM degradation after caveolin 1 knock-down was efficiently reverted by simple provision of cholesterol. In addition, the inhibitory effect of caveolin 3(DGV) expression, a mutant known to block cholesterol transport to the plasma membrane, was similarly reverted by provision of cholesterol. We suggest that invadopodia biogenesis, function and structural integrity rely on appropriate levels of plasma membrane cholesterol, and that invadopodia display the properties of cholesterol-rich membranes. Also, caveolin 1 exerts its function in invadopodia formation by regulating cholesterol balance at the plasma membrane. These findings support the connection between cholesterol, cancer and caveolin 1, provide further understanding of the role of cholesterol in cancer progression and suggest a mechanistic framework for the proposed anti-cancer activity of statins, tightly related to their blood cholesterol-lowering properties.
authors.affiliation: Tumor Cell Invasion Laboratory, Department of Cell Biology and Oncology, Consorzio Mario Negri Sud, Chieti, Italy.
authors.forename: Giusi
authors.initials: G
authors.lastname: Caldieri
authors.affiliation: Tumor Cell Invasion Laboratory, Department of Cell Biology and Oncology, Consorzio Mario Negri Sud, Chieti, Italy.
authors.forename: Giada
authors.initials: G
authors.lastname: Giacchetti
authors.affiliation: Tumor Cell Invasion Laboratory, Department of Cell Biology and Oncology, Consorzio Mario Negri Sud, Chieti, Italy.
authors.forename: Galina
authors.initials: G
authors.lastname: Beznoussenko
authors.affiliation: Tumor Cell Invasion Laboratory, Department of Cell Biology and Oncology, Consorzio Mario Negri Sud, Chieti, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Attanasio
authors.affiliation: Tumor Cell Invasion Laboratory, Department of Cell Biology and Oncology, Consorzio Mario Negri Sud, Chieti, Italy.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Ayala
authors.affiliation: Tumor Cell Invasion Laboratory, Department of Cell Biology and Oncology, Consorzio Mario Negri Sud, Chieti, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Buccione
mesh_terms: D022461:Caveolins / Q000502:physiology*; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism*; D006801:Humans; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D008563:Membrane Lipids / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis
chemical_list: D022461:Caveolins; D008563:Membrane Lipids; D002784:Cholesterol