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

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.

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Journal
eLife
Published
2025-03-07
DOI
https://doi.org/10.7554/elife.102205.3
Citations
4
Primary Topic
Glycosylation and Glycoproteins Research
Type
article
Field-Weighted Citation Impact
3.22

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article

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

Gizem Oyman-Eyrilmez, Lenka Sarnová, Martin Gregor, Samuel M. Meier et al.
4 citations
eLife
Glycosylation and Glycoproteins Research
3.22
article

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

Gizem Oyman-Eyrilmez, Lenka Sarnová, Martin Gregor, Samuel M. Meier, Petra Novotná, Daniel Rösel, Zuzana Outla, Mathias Heikenwälder, Andrea Gálisová, Katerina Korelova, Jan Kosla, Magdalena Přechová, Patricia Bortel, Christopher Gerner, Daniel Jirák, Yasmin Borutzki, Emrullah Birgin, Nuh N. Rahbari, Lukas Frick, Piyush Bisht, Ondřej Tolde, Eva Sticová, Kateřina Sulková, Njainday Jobe, Andrea Bileck, Gerhard Wiche, Martin Otáhal, Mohammad Rahbari, Andreas Bauer, Tracy O’Connor, Bibiana Kvasnicova
article en
4 citations

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.

eLifeVol. 13
University of Vienna (AT), North Park University (US), German Cancer Research Center (DE), Friedrich-Alexander-Universität Erlangen-Nürnberg (DE), University of Zurich (CH), Charles University (CZ), Heidelberg University (DE), University Hospital Heidelberg (DE), Max Perutz Labs (AT), Institute of Inorganic Chemistry of the Slovak Academy of Sciences (SK), Institute of Clinical and Experimental Medicine (CZ), Institute of Molecular Genetics (RU), University Hospital Ulm (DE), Czech Technical University in Prague (CZ), Medical University of Vienna (AT)
Ministerstvo Školství, Mládeže a Tělovýchovy, Grantová Agentura České Republiky, Ministerstvo Zdravotnictví Ceské Republiky, European Regional Development Fund
Openalex Percentile: Top 9%
Glycosylation and Glycoproteins Research
3.22
DOIOpen Access PDFOpenAlex
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