Inside the Cell: Integrins as New Governors of Nuclear Alterations?

Abstract

Cancer cell migration is a complex process that requires coordinated structural changes and signals in multiple cellular compartments. The nucleus is the biggest and stiffest organelle of the cell and might alter its physical properties to allow cancer cell movement. Integrins are transmembrane receptors that mediate cell-cell and cell-extracellular matrix interactions, which regulate numerous intracellular signals and biological functions under physiological conditions. Moreover, integrins orchestrate changes in tumor cells and their microenvironment that lead to cancer growth, survival and invasiveness. Most of the research efforts have focused on targeting integrin-mediated adhesion and signaling. Recent exciting data suggest the crucial role of integrins in controlling internal cellular structures and nuclear alterations during cancer cell migration. Here we review the emerging role of integrins in nuclear biology. We highlight increasing evidence that integrins are critical for changes in multiple nuclear components, the positioning of the nucleus and its mechanical properties during cancer cell migration. Finally, we discuss how integrins are integral proteins linking the plasma membrane and the nucleus, and how they control cell migration to enable cancer invasion and infiltration. The functional connections between these cell receptors and the nucleus will serve to define new attractive therapeutic targets.

Keywords: ECM; chromatin; integrins; nuclear deformability; nuclear mechanics; nucleus; tumor microenvironment.

Figure 1

Schematic representation of the interplay between integrins and nuclear changes. Multiple external stimuli from the tumor microenvironment control integrin-mediated signals. The cytoskeleton and protein kinases transmit these signals from the cell surface into the nucleus. These downstream pathways contribute to (I) nuclear mechanics and deformability (mainly regulated by lamins, LINC (Linker of nucleoskeleton and cytoskeleton) complexes, the perinuclear cytoskeleton and the chromatin); (II) the rotation and movement of the nucleus (critical for specific cell migration types, such as lobopodial migration); and (III) the intranuclear disposition. Together, the interplay between integrins and nucleus support cancer cell migration and dissemination through constricted conditions.