Plectin-mediated cytoskeletal crosstalk as a target for inhibition of hepatocellular carcinoma growth and metastasis

Outla Z, Oyman-Eyrilmez G, Korelova K, Prechova M, Frick L, Sarnova L, Bisht P, Novotna P, Kosla J, Bortel P, Borutzki Y, Bileck A, Gerner C, Rahbari M, Rahbari N, Birgin E, Kvasnicova B, Galisova A, Sulkova K, Bauer A, Jobe N, Tolde O, Sticova E, Rösel D, O'Connor T, Otahal M, Jirak D, Heikenwälder M, Wiche G, Meier-Menches SM, Gregor M (2025)

Publication Type: Journal article

Publication year: 2025

Journal

eLife eLife Sciences Publications

Book Volume: 13

DOI: 10.7554/eLife.102205

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.

Authors with CRIS profile

Andreas Bauer Lehrstuhl für Biophysik

Involved external institutions

Universität Wien / University of Vienna AT Austria (AT) Deutsches Krebsforschungszentrum (DKFZ) DE Germany (DE) Institute of Molecular Genetics of the ASCR / Ústav molekulární genetiky AV ČR CZ Czech Republic (CZ) University of Zurich / Universität Zürich (UZH) CH Switzerland (CH) Universitätsklinikum Ulm DE Germany (DE) Czech Technical University in Prague / České vysoké učení technické v Praze CZ Czech Republic (CZ) Institute for Clinical and Experimental Medicine (IKEM) CZ Czech Republic (CZ) Univerzita Karlova v Praze / Charles University in Prague CZ Czech Republic (CZ) North Park University (NPU) US United States (USA) (US) Max Perutz Labs / Max F. Perutz Laboratories (MFPL) AT Austria (AT)

How to cite

APA:

Outla, Z., Oyman-Eyrilmez, G., Korelova, K., Prechova, M., Frick, L., Sarnova, L.,... Gregor, M. (2025). Plectin-mediated cytoskeletal crosstalk as a target for inhibition of hepatocellular carcinoma growth and metastasis. eLife, 13. https://doi.org/10.7554/eLife.102205

MLA:

Outla, Zuzana, et al. "Plectin-mediated cytoskeletal crosstalk as a target for inhibition of hepatocellular carcinoma growth and metastasis." eLife 13 (2025).

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