In the context of bone tissue, lamins play a crucial role in bone differentiation and development (Alcorta-Sevillano et al., 2020). In particular, Lamin A/C is essential at different levels during MSCs’ commitment and during the maturation of osteoblasts. MSCs navigate towards stiffer regions of substrates, transitioning from a soft matrix (1 kPa) to a rigid matrix (34 kPa), by orienting the cytoskeleton (Raab et al., 2012). Given that Lamin A/C is intricately associated with the cytoskeleton through the LINC complex, it plays a role in cellular responses to matrix elasticity. Recent research indicates that physical and mechanical cues from the microenvironment are pivotal in determining MSC fate, suggesting a close relationship between the mechanical cues and the specific lineage differentiation of MSCs (Vahabikashi et al., 2022). Indeed, the nucleus serves as the primary regulator of cell fate, as it governs gene expression and its ability to react to external signals (Rubin et al., 2022). LaminA/C deficiency in MSCs and mature osteoblasts causes a dramatic reduction in the expression of specific bone cell markers, such as genes involved in mineralization and alkaline phosphatase expression, and of bone differentiation master genes (as OCN, OSX, and BSP) (Akter et al., 2009). Furthermore, the absence of Lamin A/C has important side effects on both osteoblasts and osteoclasts. In fact, osteoblasts are less differentiated and, as a consequence, osteoclastogenesis is enhanced (Rauner et al., 2009). Indeed, Lamin A/C influences the regulation of two proteins that control osteoclastogenesis: receptor activator of nuclear factor κ-B ligand (RANKL) and osteoprotegerin (OPG) (Akter et al., 2009). RANKL is produced by immature osteoblasts; therefore, when Lamin A/C is inhibited, osteoblast differentiation is arrested, resulting in an elevated level of RANKL, disrupting the balance of the RANKL/OPG ratio and fostering an osteoclastogenic environment. In contrast, Lamin A/C overexpression in mouse pre-osteoblastic MC3T3-E1 cells has been demonstrated to enhances osteoblast differentiation and mineralization by stimulating the expression of alkaline phosphatase, type I collagen, BSP, OCN, and dentin matrix acidic phosphoprotein 1 (DMP-1) in the presence of bone morphogenetic protein 2 (BMP-2) growth factor (Tsukune et al., 2017). The main involvement of Lamin A/C in bone tissue is shown in Figure 1A. Moreover, Lamin A/C and LINC complexes are also responsible for the nuclear entry of β-catenin, YAP/TAZ, and Notch signalling, all of which play pivotal roles in osteoblast differentiation and maturation (Bermeo et al., 2015; Uzer et al., 2018; Swift et al., 2013). These evidences together pointout the importance of Lamin A/C in the maintenance of bone tissue homeostasis. Given the critical role of lamins in nuclear architecture and cellular function, mutations or dysregulation of these proteins can result in pathological conditions. Disorders arising from mutations in lamin genes are collectively referred to as laminopathies. The most studied one is HGPS, characterized by the accumulation of an immature form of Lamin A/C (pre-Lamin A/C) within the nucleus. This disease primarily affects bone and muscle (Eriksson et al., 2003). Beyond laminopathies, lamins can also be dysregulated in tumours, and in recent years there has been growing interest and research into their role in cancer.

The role of lamins in cancer is highly heterogeneous and closely depends on the specific type of cancer being examined. Experimental evidence of lamin deregulation has been found in several tumours, such as gastric, lung and pelvis carcinomas, resumed in Table 1. In lung adenocarcinoma, LMNB1 silencing inhibited cancer cell proliferation and migration (Tang et al., 2021). Anyway, the role of LMNB1 in lung cancer is controversial as other studies consider it as an onco-suppressor (Jia et al., 2019). While low levels of LMNA in lung cancer are associated with a poorer prognosis and more metastasis to bone (Kaspi et al., 2017). Moreover, a similar behaviour seems to be applied also in colorectal cancer by LMNB2 regulating p21 and promoting the cancer progression (Dong et al., 2021), also LMNA is considered a risk biomarker in colorectal cancer (Willis et al., 2008). There is contrasting evidence regarding colon cancer where the lower levels of LMNA expression were demonstrated to be related to a poorer prognosis (Belt et al., 2011). In hepato-cellular carcinoma (HCC), lamin family genes showed elevated expression levels. Prognostic evaluations indicated that LMNB1 and LMNB2 serve as indicators for poor clinical outcomes (Yang et al., 2022). It was demonstrated that combined targeting of LMNB2 alongside with a drug inhibition of PD1 exhibited a synergistic impact on hindering tumour advancement both in vivo and in vitro, especially in HCC models characterized by LMNB2 overexpression (Li et al., 2025). Regarding LMNA in HCC, this is considered an oncogene as its knockout cause a reduction in proliferation and migration capability of HepG2 cells (Liu et al., 2020). Interestingly, in prostate cancer the overexpression of LMNA is associated to a worst prognosis. In fact, has been demonstrated a correlation between the expression of LMNA in aggressive cancers and the invasiveness of tumours through the PI3K/AKT/PTEN pathway, suggesting that targeting LMNA could represent a chance to counteract the invasiveness of cancer (Kong et al., 2012). Also, LMNB1 is associated with tumour progression and metastasis in prostate cancer (Luo et al., 2021). Thereafter, even in breast cancer lamins deregulation was found. In particular, was demonstrated that highly invasive and rapidly proliferating breast cancer cells often display reduced levels of LMNA, which results in increased nuclear deformability, and as said before, this corresponds to an increased cell migration. Notably, elevating LaminA/C levels in highly invasive breast cancer cells specifically impact pathways associated with cell-ECM interactions and cellular metabolism (Bell et al., 2022; Setijono et al., 2018). Lastly, in ovarian cancer (OC) it is reported that higher levels of LMNB1 are associated with the advancement of the disease. Reducing LMNB1 expression slows down the growth and migration of OC cells. Moreover, in ovarian cancer LMNB1 is considered as a new potential prognostic marker and therapeutic target (Dong et al., 2023). Regarding LMNA in ovarian cancer, is known that its downregulation represents the trigger for nuclear abnormalities (Capo-chichi et al., 2011). Deeply, recent finding suggest that LMNA contributes to metastasis via nuclear morphologic changes (Ouchi et al., 2023).

At present, there are still few studies that have investigated the role of lamins in osteosarcoma but, given their relevance in the bone homeostasis, this could be key-pivotal point to be deepened in this field. Firstly, Urciuoli and co-authors demonstrated that osteosarcoma cell lines show a different lamin’s expression in comparison to normal osteoblasts. More in detail, Lamin A/C expression seems to be inversely related to the aggressiveness of tumour cell line, indeed the more metastatic ones have less content of Lamin A/C, while the Lamin B expression is always upregulated. The forced expression of Lamin A/C in high aggressive cell line reduces tumour features, such as proliferation and migration, and restores cell adhesion on substrate with bone tissue elasticity, meanwhile LaminA/C silencing in SaOS-2 (cells with low grade of aggressiveness) increases the proliferation rate (Urciuoli et al., 2021). Moreover, a correlation was also demonstrated between the expression of Lamin A/C and Emerin, YAP and Rb nuclear content (Urciuoli et al., 2020). In fact, their nuclear localization was reduced in A-type lamin deficient cells. As described before the nuclear content of YAP is regulated by A-type lamin and, as widely demonstrated, YAP is a mechanosensor protein important not only for the correct development of bone tissue (Dupont et al., 2011). These results suggest that Lamin A/C could play a role in OS progression, by then another study by Evangelisti et al., confirmed that elevated levels of Lamin A/C are directly involved in the migration and proliferation of OS cells (Evangelisti et al., 2020). There is another evidence in literature about the osteosarcoma and Lamin A/C expression. In this paper, the interaction between CNOT1 (transcription complex) in osteosarcoma cells was examined. They demonstrated that CNOT1 interacts with Lamin A/C and affects its stability, in fact, when CNOT1 is knockdown the levels of Lamin A/C decrease. The restoration of Lamin A/C protein expression in CNOT1-knockdown cells promoted tumour cell growth. The silencing of CNOT1 reduce osteosarcoma cell proliferation by blocking the Hedgehog signalling pathway through Lamin A/C. They suggest that strategies aiming at the CNOT1– Lamin A/C–Hedgehog signalling pathway axis may represent a practical and effective approach for osteosarcoma treatment (Cheng et al., 2017). This data gives to Lamin A/C a different role in osteosarcoma, which goes in contrast with the other available data. The main known function of Lamin A/C in OS are described in Figure 1B. Regarding the Lamin B1 in osteosarcoma has been demonstrated to modulate nucleotide excision repair (NER) in response to ultraviolet damage by adjusting the expression of genes related to NER (Butin-Israeli et al., 2013). Recent studies indicate that OS cells exploit DNA repair systems, such as NER, to evade DNA-damaging chemotherapeutics treatments, like cisplatin. A promising treatment approach may involve targeting NER components (Hattinger et al., 2020). Fanelli and co-authors recently discovered that two compounds, NSC130813 (NERI02; F06) and triptolide, which inhibit DNA repair by binding to DNA repair proteins, increase sensitivity to cisplatin in U2OS and SaOS-2 cells (Fanelli et al., 2020). Gaining insights into how these elements operate within the framework of mechanotransduction could enhance the efficacy of NSC130813 (NERI02; F06) and triptolide in treating resistant OSA patients. Another study conducted on Ewing’s sarcoma, which is another bone tumour, investigated the role of Lamin A/C in the metastatic process of Ewing’s sarcoma (EWS). They demonstrated that Lamin A/C expression is inversely correlated with tumour invasiveness in EWS patients. Into deep, Lamin A/C expression was significantly lower in metastatic tissues compared to primary tumours, and reduced Lamin A/C expression was associated with increased mobility and invasiveness of EWS cells. Furthermore, overexpression of Lamin A/C decreased motility and invasiveness of EWS cells in vitro and metastatic burden in vivo, particularly in liver metastases. This effect may be mediated by liver growth factors such as IGF and HGF/SF. The drug mevinolin, which increases pre-Lamin A/C levels, showed similar effects by reducing EWS cell migration and inducing neural differentiation, suggesting that Lamin A/C may promote differentiation in EWS cells. The study also highlighted the role of Lamin A/C in influencing the LINC complex, which regulates cytoskeleton dynamics and cell migration. Treatment with mevinolin reduced YAP/TAZ signaling activity, which is linked to tumor progression, and led to Lamin A/C accumulation. This treatment also reduced cell motility. In summary, the study identifies Lamin A/C’s role in the metastatic process of EWS and suggests that drugs like mevinolin, which modulate Lamin A/C, could be potential therapies for metastatic EWS cases (Chiarini et al., 2022).