Plectin-mediated cytoskeletal crosstalk as a target for inhibition of hepatocellular carcinoma growth and metastasis
- Author(s)
- Zuzana Outla, Gizem Oyman-Eyrilmez, Katerina Korelova, Magdalena Prechova, Lukas Frick, Lenka Sarnova, Piyush Bisht, Petra Novotna, Jan Kosla, Patricia Janker-Bortel, Yasmin Borutzki, Andrea Bileck, Christopher Gerner, Mohammad Rahbari, Nuh Rahbari, Emrullah Birgin, Bibiana Kvasnicova, Andrea Galisova, Katerina Sulkova, Andreas Bauer, Njainday Jobe, Ondrej Tolde, Eva Sticova, Daniel Rösel, Tracy O'Connor, Martin Otahal, Daniel Jirak, Mathias Heikenwälder, Gerhard Wiche, Samuel M. Meier-Menches, Martin Gregor
- Abstract
The most common primary malignancy of the liver, hepatocellular carcinoma (HCC), is a heterogeneous tumor entity with high metastatic potential and complex pathophysiology. Increasing evidence suggests that tissue mechanics plays a critical role in tumor onset and progression. Here, we show that plectin, a major cytoskeletal crosslinker protein, plays a crucial role in mechanical homeostasis and mechanosensitive oncogenic signaling that drives hepatocarcinogenesis. Our expression analyses revealed elevated plectin levels in liver tumors, which correlated with poor prognosis for HCC patients. Using autochthonous and orthotopic mouse models we demonstrated that genetic and pharmacological inactivation of plectin potently suppressed the initiation and growth of HCC. Moreover, plectin targeting potently inhibited the invasion potential of human HCC cells and reduced their metastatic outgrowth in the lung. Proteomic and phosphoproteomic profiling linked plectin-dependent disruption of cytoskeletal networks to attenuation of oncogenic FAK, MAPK/Erk, and PI3K/Akt signatures. Importantly, by combining cell line-based and murine HCC models, we show that plectin inhibitor plecstatin-1 (PST) is well-tolerated and potently inhibits HCC progression. In conclusion, our study demonstrates that plectin-controlled cytoarchitecture is a key determinant of HCC development and suggests that pharmacologically induced disruption of mechanical homeostasis may represent a new therapeutic strategy for HCC treatment.
- Organisation(s)
- Department of Analytical Chemistry, Department of Inorganic Chemistry, Joint Metabolome Facility, Department of Biochemistry and Cell Biology
- External organisation(s)
- Institute of Molecular Genetics of the Czech Academy of Sciences, Universität Zürich (UZH), Stiftung Deutsches Krebsforschungszentrum, Scientific Software Center, Universitätsklinikum Ulm, Czech Technical University in Prague (CTU), Institute for Clinical and Experimental Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Charles University Prague, North Park University
- Journal
- eLife
- Volume
- 13
- ISSN
- 2050-084X
- DOI
- https://doi.org/10.7554/eLife.102205
- Publication date
- 03-2025
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 301904 Cancer research, 301303 Medical biochemistry, 301306 Medical molecular biology
- Keywords
- ASJC Scopus subject areas
- General Neuroscience, General Biochemistry,Genetics and Molecular Biology, General Immunology and Microbiology
- Sustainable Development Goals
- SDG 3 - Good Health and Well-being
- Portal url
- https://ucrisportal.univie.ac.at/en/publications/ed1ad160-92ae-4851-bfb8-2eac8f078a02