Senescent stroma induces nuclear deformations in cancer cells via the inhibition of RhoA/ROCK/myosin II-based cytoskeletal tension

The presence of senescent cells within tissues has been functionally linked to malignant transformations. Here, using tension-gauge tethers technology, particle-tracking microrheology, and quantitative microscopy, we demonstrate that senescent-associated secretory phenotype (SASP) derived from senescent fibroblasts impose nuclear lobulations and volume shrinkage on malignant cells, which stems from the loss of RhoA/ROCK/myosin II-based cortical tension. This loss in cytoskeletal tension induces decreased cellular contractility, adhesion, and increased mechanical compliance. These SASP-induced morphological changes are, in part, mediated by Lamin A/C. These findings suggest that SASP induces defective outside-in mechanotransduction from actomyosin fibers in the cytoplasm to the nuclear lamina, thereby triggering a cascade of biophysical and biomolecular changes in cells that associate with malignant transformations. Significance Statement: Senescent cells promote adverse physiologies and malignant transformations in many organisms. During ageing, senescent cells accumulate and impose mechano-structural alterations on their local microenvironment, mainly through the hyper-secretion of soluble factors that influence the phenotypes of neighboring cells. Here we show that secreted factors from senescent cells induce a defective outside-in signaling cascade to promote nuclear lobulations in cancer cells. These nuclear lobulations result from the loss of cytoskeletal tension through and decreased RhoA/ROCK/Myosin II-based contractility and are capable of triggering a cascade of changes in cells, ranging from cytoskeletal-induced changes in morphologies that associates with the propagation of malignant transformations and phenotype-switching in cancer cells.