Targeting nucleocytoplasmic barrier function in cancer

• Applicant: Professor Dr. Victor Shahin
• Subject Area: Anatomy and Physiology ; Pharmacy
• Term: since 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 261683348

Malignant transformation is a multistep process involving a multitude of intracellular factors and affecting several fundamental aspects of cellular physiology. Consequently, malignant transformation poses considerable challenges for therapeutic intervention. Finding a single point of therapeutic assault among the plethora of dysregulated signaling pathways poses a substantial challenge. Therefore, complementing the targeting of the individual components of carcinogenic signaling pathways with the targeting of the intracellular infrastructural nodes enabling this signaling could produce a more robust therapeutic outcome. One of such key hubs of the cellular infrastructure are the nuclear pore complexes (NPCs) mediating all of the nucleocytoplasmic communication. Despite the overwhelming amount of evidence pointing towards the critical importance of signaling across the nuclear envelope for promoting malignant transformation, the actual involvement of the NPCs is far from being adequately characterized. Preliminary data generated in preparation of this project strongly indicates that a critical ability of the NPCs to exclude substances from the nuclear interior is compromised in cancerous cells. Interestingly, the severity of the defect correlates with the aggressiveness of the malignant phenotype displayed by the tested cell lines. Therefore, the aim of this project is to investigate a putative involvement of the NPCs in enhancing the severity of the malignant phenotype. Understanding the ways cancer cells exploit this particular element of cellular communication infrastructure may lead to improved intranuclear delivery of the existing therapeutics. More importantly, novel strategies for targeting the nucleocytoplasmic communication may be devised for a more specific combating of cancer.

• DFG Programme: Research Grants