Nuclear pore complexes (NPCs) are of particular physiological importance. They form highly selective transport barrier for all molecules between the cytosol and the nucleus thereby safeguarding the enclosed nuclear DNA. Several NPC proteins are potent gene transcription regulators and are thus of substantial importance for development, differentiation and maintenance of cells. Their expression beyond or below physiological levels is linked to cancer onset and progression. These links, however, remain unclear. Exploring the links between NPCs and cancer has therefore become an attractive target in cancer research. Our goal is to shed light onto the relationship between NPCs and cancer. We therefore set out to study from multiple aspects the differences between NPCs in non-metastatic compared to highly aggressive non-small human lung cancer cell lines. Our findings demonstrate that transformation in NPCs barrier function, permeability and molecular composition promotes malignancy of lung cancer cells. Moreover, controlled breakdown of NPC barrier function following exposure to certain drugs prevents cancer cell migration. The observations made here present direct links between NPCs transformation and cancer malignancy and may usher in the design of new strategies for the treatment of cancer.