Abstract
Besides its structural properties in the nucleoskeleton, Lamin A/C is a mechanosensor protein involved in perceiving the elasticity of the extracellular matrix. In this study we provide evidence about Lamin A/C-mediated regulation of osteosarcoma cell adhesion and spreading on substrates with tissue-specific elasticities. Our working hypothesis is based on the observation that low-aggressive and bone-resident SaOS-2 osteosarcoma cells express high level of Lamin A/C in comparison to highly metastatic, preferentially to the lung, osteosarcoma 143B cells, thereby suggesting a role for Lamin A/C in tumor cell tropism. Specifically, LMNA gene over-expression in 143B cells induced a reduction in tumor cell aggressiveness in comparison to parental cells, with decreased proliferation rate and reduced migration capability. Furthermore, LMNA reintegration into 143B cells changed the adhesion properties of tumor cells, from a preferential tropism toward the 1.5 kPa PDMS substrate (resembling normal lung parenchyma) to the 28 kPa (resembling pre-mineralized bone osteoid matrix). Our study suggests that Lamin A/C expression could be involved in the organ tropism of tumor cells, thereby providing a rationale for further studies focused on the definition of cancer mechanism of metastatization.
Highlights
Lamins are nuclear type V intermediate filament protein that bridge chromatin to the inner nuclear membrane by forming a protein scaffold at the nuclear periphery, called the nuclear lamina (Gruenbaum et al, 2005; Dahl and Kalinowski, 2011; Gruenbaum and Foisner, 2015)
Lamin A/C differential amounts in osteosarcoma cells were confirmed at a transcriptional level by qRT-PCR analysis (Figure 1C), prompting us to further analyze the effects of LMNA gene modulation in tumor cells aggressiveness
Lamin A/C levels are described as risk biomarkers for colorectal cancer patients, given that patients with A-type lamin-expressing tumors have significantly worse prognosis than patients with A-type lamin negative tumors and Lamin A/C overexpression in a colorectal cancer cell line increases cell motility and invasion by downregulating cell adhesion (Willis et al, 2008)
Summary
Lamins are nuclear type V intermediate filament protein that bridge chromatin to the inner nuclear membrane by forming a protein scaffold at the nuclear periphery, called the nuclear lamina (Gruenbaum et al, 2005; Dahl and Kalinowski, 2011; Gruenbaum and Foisner, 2015). A- and B-type lamins differ greatly in their expression patterns, biochemical features, and behavior during mitosis. The A-type lamins are among the most mutated human genes, and their mutations cause genetic disorders termed laminopathies, affecting muscle, fat, neuron, bone, and skin tissues, and ranging from muscular dystrophies to lipodystrophies neuropathies and early aging diseases (Worman and Bonne, 2007). Besides their structural roles in providing a mechanical support to the nucleoskeleton, lamins have been recently recognized as regulators of gene expression and mechanical sensors for tissue elasticity. Several works have clearly demonstrated that lamin A expression functions as a “mechanostat,” revealing that matrix stiffness and mechanical stress are able to regulate Lamin A expression, thereby stabilizing the nucleus and contributing to cell lineage determination (Swift et al, 2013; Swift and Discher, 2014; Ivanovska et al, 2017; Xia et al, 2018; Cho et al, 2019; Gumina et al, 2021)
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