Lamin A, a main constituent of the nuclear lamina, is involved in mechanosignaling and cell migration through dynamic interactions with the LINC complex, formed by the nuclear envelope
proteins SUN1, SUN2 and the nesprins. Here, we investigated
lamin A role in
Ewing Sarcoma (EWS), an aggressive bone
tumor affecting children and young adults. In patients affected by EWS, we found a significant inverse correlation between LMNA gene expression and
tumor aggressiveness. Accordingly, in experimental in vitro models, low
lamin A expression correlated with enhanced cell migration and invasiveness and, in vivo, with an increased metastatic load. At the molecular level, this condition was linked to altered expression and anchorage of nuclear envelope
proteins and increased nuclear retention of YAP/TAZ, a mechanosignaling effector. Conversely, overexpression of
lamin A rescued LINC complex organization, thus reducing YAP/TAZ nuclear recruitment and preventing cell invasiveness. These effects were also obtained through modulation of
lamin A maturation by a
statin-based pharmacological treatment that further elicited a more differentiated phenotype in EWS cells. These results demonstrate that drugs inducing nuclear envelope remodeling could be exploited to improve therapeutic strategies for EWS.