Nucleoporin-93 overexpression overcomes trafficking bottlenecks in metastasis of breast cancer

The integrative computational analysis we developed has assigned NUP93 with important roles in progression of mammary cancer, which we confirmed in animals. Surprisingly, NUP93 emerges from these studies as a master driver of metastasis. This conclusion was supported by functional characterization of two groups of naturally occurring mutant alleles. Remarkably, mammary cells overexpressing NUP93 display over-activation of multiple growth factor pathways, including the WNT/beta-catenin pathway. This route has previously been associated with colorectal tumors, but recent network-based analysis linked it to breast cancer (Koval and Katanaev, 2018). We conclude that NUP93 integrates and enhances not only WNT but also additional growth factor signals. Thus, by seizing an essential step common to multiple signaling routes, NUP93 acquires robust oncogenic attributes. Beyond the identification of augmented nuclear transport as a new hallmark of cancer, our study exposes tumor vulnerabilities and offers not only a new target for intervention but also a pharmacological strategy tailored to the subset of NUP93 overexpressors. WCE RNA was extracted from MDA-MB-231 cells treated with either control or NUP93-targetting siRNA, in two biological replicates. In addition, MCF7 cells were similarly treated fith siRNAs and fractionated to obtain WCE, cytosolic and nuclear fractions. RNA was extracted from all fractions (two biological replicates), and all samples were subjected to RNA-seq after PolyA selection.