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Sci Rep. 2019 May 21;9(1):7667. doi: 10.1038/s41598-019-43409-x.

TGFβ-induced cytoskeletal remodeling mediates elevation of cell stiffness and invasiveness in NSCLC.

Author information

1
German Cancer Research Center, Div. Bioinformatics and Omics Data Analytics, Mathematikon - Berliner Str. 41, 69120, Heidelberg, Germany. evgeny.gladilin@gmail.com.
2
University Heidelberg, BioQuant, Im Neuenheimer Feld 267, 69120, Heidelberg, Germany. evgeny.gladilin@gmail.com.
3
Leibniz Institute of Plant Genetics and Crop Plant Research, OT Gatersleben Corrensstrasse 3, 06466, Seeland, Germany. evgeny.gladilin@gmail.com.
4
University of Freiburg, Institute of Molecular Medicine and Cell Research (IMMZ), Stefan-Meier-Str. 17, 79104, Freiburg, Germany.
5
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
6
Department for Biometry, Epidemiology and Medical Bioinformatics and Comprehensive Cancer Center Freiburg (CCCF), University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Breisacherstrasse 153, 79110, Freiburg, Germany.
7
University of Lübeck, Institute of Experimental Dermatology, Ratzeburger Allee 160, 23538, Lübeck, Germany.
8
Thoraxklinik at Heidelberg University Hospital, Amalienstr. 5, 69126, Heidelberg, Germany.
9
Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany.
10
Center for Digital Health, Berlin Institute of Health, and Charité Universitätsmedizin Berlin, Kapelle-Ufer 2, 10117, Berlin, Germany.
11
Health Data Science Unit, Heidelberg University Hospital, Im Neuenheimer Feld 267, 69120, Heidelberg, Germany.

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.

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