Nucleoporin-93 Overcomes Multiple Nucleocytoplasmic Trafficking Bottlenecks and Permits Robust Metastasis

To identify genetic events driving breast cancer progression, we performed multi-omics integrated analyses that identified overexpression of nucleoporin-93, a nuclear pore component. We show that NUP93 overexpression enhances trans-endothelial migration and matrix invasion, along with metastasis in animal models. These findings were supported by analyses of two sets of naturally occurring mutations: oncogenic mutations and inactivating nephrotic syndrome mutations. Mechanistically, NUP93 activation enhanced the ultimate nuclear transport step shared by multiple signaling pathways, including TGF-beta/SMAD, EGF/ERK and TNF/NF-kB. Likewise, NUP93 boosts nuclear transport of beta-catenin, as well as elevates expression and inhibit degradation of this co-activator. 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 inhibited growth and metastasis. Our study sheds light on a previously unappreciated hallmark of advanced tumors, which derive benefit from unblocking a set of nucleocytoplasmic bottlenecks.