Nucleus is a specialized organelle that serves as a control tower of all the cell behavior. While traditional biochemical features of nuclear signaling have been unveiled, many of the physical aspects of nuclear system are still under question. Innovative biophysical studies have recently identified mechano-regulation pathways that turn out to be critical in cell migration, particularly in cancer invasion and metastasis. Moreover, to take a deeper look onto the oncologic relevance of the nucleus, there has been a shift in cell systems. That is, our understanding of nucleus does not stand alone but it is understood by the relationship between cell and its microenvironment in the in vivo-relevant 3D space.