Unravelling new mechanisms in bone cancer progression

Osteosarcoma (OS) and Ewing Sarcoma (EWS) are the most frequent primary bone tumors affecting pediatric patients. Lamin A, a nuclear protein constituting the nuclear lamina, plays a key role in maintaining nuclear shape, organizing the nuclear envelope (NE), and ensuring mechanical stability. The interplay between lamins and LINC (linker of nucleoskeleton and cytoskeleton) complex proteins facilitates the transmission of mechanical signals from the extracellular matrix to the nucleus. It’s disruption can significantly affect migration and invasiveness involved in tumor progression. We explored the role of NE proteins in OS, investigating how alterations in lamin A levels influence the expression and localization of LINC complex. We found reduced lamin A levels in OS, compared to osteoblasts, while its overexpression influences LINC complex protein expression and localization, leading to decreased invasiveness. Also, differentiated OS cells, showed an upregulation of lamin A, and a significant modulation of LINC complex, similarly to the effects obtained with the overexpression of lamin A. Thus, restoring physiological NE could prove crucial for OS, where non-toxic, differentiation-based strategies are urgently needed. In addition, we turned our attention to the aggressive nature of EWS, which is profoundly influenced by epigenetic mechanisms. Thus, we investigated the role of UHRF1, a key player in epigenetic reprograming and in tumor progression across various cancers. UHRF1 is known to regulate gene expression through DNA methylation, and acts as a cell cycle controller, impacting cell growth, apoptosis, DNA repair, and histone modifications. We assessed UHRF1 expression in EWS patients and found that it is upregulated in metastatic versus primary EWS tumors, affecting patient survival. Our transcriptomic analysis of EWS cells knocked-down for UHRF1 revealed a significant modulation of various effectors involved in EWS progression, warranting further investigation.