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Abstract
Importance of growth factor (GF) signaling in cancer progression is widely acknowledged. Transforming growth factor beta (TGFβ) is known to play a key role in epithelial-to-mesenchymal transition (EMT) and metastatic cell transformation that are characterized by alterations in cell mechanical architecture and behavior towards a more robust and motile single cell phenotype. However, mechanisms mediating cancer type specific enhancement of cell mechanical phenotype in response to TGFβ remain poorly understood. Here, we combine high-throughput mechanical cell phenotyping, microarray analysis and gene-silencing to dissect cytoskeletal mediators of TGFβ-induced changes in mechanical properties of on-small-cell lung carcinoma (NSCLC) cells. Our experimental results show that elevation of rigidity and invasiveness of TGFβ-stimulated NSCLC cells correlates with upregulation of several cytoskeletal and motor proteins including vimentin, a canonical marker of EMT, and less-known unconventional myosins. Selective probing of gene-silenced cells lead to identification of unconventional myosin MYH15 as a novel mediator of elevated cell rigidity and invasiveness in TGFβ-stimulated NSCLC cells. Our experimental results provide insights into TGFβ-induced cytoskeletal remodeling of NSCLC cells and suggest that mediators of elevated cell stiffness and migratory activity such as unconventional cytoskeletal and motor proteins may represent promising pharmaceutical targets for restraining invasive spread of lung cancer.
Highlights
Non-small-cell lung adenocarcinoma (NSCLC) is the leading cause of cancer-related mortalities worldwide[1]
Our findings provide a comprehensive picture of phenotypic effects and genomic response of NSCLC cells to Transforming Growth Factor β (TGFβ)- and Hepatocyte Growth Factor (HGF)-stimulation that sheds light on the mechanisms of Growth factors (GF)-induced invasive tumor spread
As TGFβ showed the strongest impact on stiffness of H1975 cells, microfluidic optical stretcher (MOS) measurements of cell compliance were extended to two additional NSCLC cell lines (H1650, H2030) as well as primary lung adenocarcinoma cells derived from two donors
Summary
Non-small-cell lung adenocarcinoma (NSCLC) is the leading cause of cancer-related mortalities worldwide[1]. Cells with amoeboid invasion are highly deformable, lack well-defined actin stress fibers and proteolytic activity[8] Instead they rely on membrane blebbing – a process of formation of bubble-like short-lived membrane protrusion[9]. We aimed to quantitatively assess alterations in the mechanical phenotype and gene expression of stable and primary NSCLC cell lines in response to single treatment and co-stimulation with the growth factors TGFβ and HGF. For this purpose, a combined approach based on high-throughput mechanical cell probing, cell migration screening, microarray analysis and gene-silencing was applied. The strongest impact on rigidity and invasiveness of NSCLC cells is observed in response to TGFβ stimulation which induces a large-scale rearrangement of cell mechanical architecture, including overexpression of vimentin intermediate filaments, adhesion/ migration relevant proteins and unconventional myosins
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