Nuclear Mechanotransduction at the Crossroads: How Membrane Receptors Remodel the Perinuclear Cytoskeleton to Drive Cancer and Disease.

Growing evidence indicates that nuclear architecture is severely altered in many pathological contexts, primarily in cancer, with major implications for chromatin arrangement and, consequently, gene expression. Actin microfilaments located in the perinuclear region at the apical surface of cells, collectively known as the "perinuclear actin cap", integrate mechanical and biochemical cues from the cell membrane and translate them into compressive forces acting on the nuclear envelope, thereby modulating nuclear shape and size. In concert with well-established mechanotransduction paradigms, these highly dynamic and finely tuned stress fibers are emerging as key players in several biological processes - from cell migration to sensing of the surrounding microenvironment - with significant implications for development, genetic disorders and tumor progression. However, how classic pathogenetic mechanisms intersect with perinuclear actin remodeling remains mostly unknown. In this review, we will describe in detail the unique functional and structural features of perinuclear actin stress fibers and recapitulate current knowledge on their upstream regulation by membrane receptors signaling. Finally, we will explore how alterations of the perinuclear actin cap may contribute to different pathogenetic processes, with a particular focus on cancer progression and metastasis.