期刊
CELL REPORTS
卷 38, 期 8, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.celrep.2022.110418
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类别
资金
- Israel Science Foundation (ISF)
- Israel Cancer Research Fund (ICRF)
- European Research Council (ERC)
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (AMRF)
By establishing multi-omics pipelines, we discovered that overexpression of NUP93 is associated with aggressive human mammary tumors, enhancing their migration and invasion capabilities. NUP93 is involved in nuclear transport, activating various signaling pathways and ultimately contributing to tumor growth and metastasis. Targeting this nuclear transport process with myristoylated peptides can inhibit tumor growth and metastasis.
By establishing multi-omics pipelines, we uncover overexpression and gene copy-number alterations of nucleoporin-93 (NUP93), a nuclear pore component, in aggressive human mammary tumors. NUP93 overexpression enhances transendothelial migration and matrix invasion in vitro , along with tumor growth and metastasis in animal models. These findings are supported by analyses of two sets of naturally occurring mutations: rare oncogenic mutations and inactivating familial nephrotic syndrome mutations. Mechanistically, NUP93 binds with importins, boosts nuclear transport of importins' cargoes, such as beta-catenin, and activates MYC. Likewise, NUP93 overexpression enhances the ultimate nuclear transport step shared by additional signaling pathways, including TGF-beta/SMAD and EGF/ERK. The emerging addiction to nuclear transport exposes vulnerabilities of NUP93-overexpressing tumors. Congruently, myristoylated peptides corresponding to the nuclear translocation signals of SMAD and ERK can inhibit tumor growth and metastasis. Our study sheds light on an emerging hallmark of advanced tumors, which derive benefit from robust nucleocytoplasmic transport.
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