Inhibition of Tunneling Nanotubes between Cancer Cell and the Endothelium Alters the Metastatic Phenotype |
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Authors: | Chinmayee Dash Tanmoy Saha Shiladitya Sengupta Hae Lin Jang |
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Affiliation: | 1.Center for Engineered Therapeutics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02139, USA; (C.D.); (T.S.);2.Division of Health Science and Technology, Harvard-Massachusetts Institute of Technology, Massachusetts Institute of Technology, Boston, MA 02139, USA;3.Dana Farber Cancer Institute, Boston, MA 02215, USA |
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Abstract: | The interaction of tumor cells with blood vessels is one of the key steps during cancer metastasis. Metastatic cancer cells exhibit phenotypic state changes during this interaction: (1) they form tunneling nanotubes (TNTs) with endothelial cells, which act as a conduit for intercellular communication; and (2) metastatic cancer cells change in order to acquire an elongated phenotype, instead of the classical cellular aggregates or mammosphere-like structures, which it forms in three-dimensional cultures. Here, we demonstrate mechanistically that a siRNA-based knockdown of the exocyst complex protein Sec3 inhibits TNT formation. Furthermore, a set of pharmacological inhibitors for Rho GTPase–exocyst complex-mediated cytoskeletal remodeling is introduced, which inhibits TNT formation, and induces the reversal of the more invasive phenotype of cancer cell (spindle-like) into a less invasive phenotype (cellular aggregates or mammosphere). Our results offer mechanistic insights into this nanoscale communication and shift of phenotypic state during cancer–endothelial interactions. |
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Keywords: | tunneling nanotube (TNT) metastasis RhoGTPase inhibitor phenotypic plasticity exocyst complex actin remodeling 3D culture mammosphere cellular aggregates |
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