Nuclear shape is one of the gold standards for detection and characterization of cancers. Nonetheless the control of nuclear morphology and its relationship to malignant behaviors are still poorly understood. We propose to study the mechanisms that lead to nuclear dysmorphia and their consequence on nuclear functions such as genome integrity and migration. The first part of the research will start from a list of actin regulators that, in preliminary experiments, showed role in controlling nuclear shape and/or DNA repair. An integrated combination of cutting edge biophysical and imaging techniques will be exploited to analyze in detail the biophysical features of nuclei and to address the potential role of the different pools of actin on nuclear shape and deformability. A relevant part of the project will be dedicated to characterize the molecular mechanisms downstream of the candidate genes and to test their role in the context of 3D migration and genome integrity.Nuclear size and stiffness represent a significant obstacle to cell migration. However, cancer cells successfully shape their nuclei to efficiently migrate through gaps with otherwise limiting dimensions. In final part of our proposal we plan to perform a RNA interference screening to isolate genes that allows migration through limiting-size pores. The candidate hits will then be studied for their role in nuclear architecture and functions.Our proposal supports the idea that the nuclear structure might be a bridge between different hallmarks of cancer and might uncover a new layer of the control of these aggressive traits in cancer.