Institute for Clinical and Experimental Medicine
Published January 1, 2025 | Version v1
Journal article Open

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

Authors/Creators

  • 1. Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic;
  • 2. Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland
  • 3. Department of Analytical Chemistry, University of Vienna, Vienna, Austria
  • 4. Institute of Inorganic Chemistry, University of Vienna, Vienna, Austria
  • 5. German Cancer Research Center, Im Neuenheimer Feld, Heidelberg, Germany
  • 6. Department of General and Visceral Surgery, Ulm University Hospital, Ulm, Germany
  • 7. Department of Natural Sciences, Faculty of Biomedical Engineering, Czech Technical University in Prague, Prague, Czech Republic
  • 8. Institut klinicke a experimentalni mediciny
  • 9. Department of Physics, University of Erlangen- Nuremberg, Erlangen, Germany
  • 10. Department of Cell Biology, Faculty of Science, Charles University, BIOCEV, Prumyslova, Vestec, Czech Republic
  • 11. Department of Biology, North Park University, Chicago, United States
  • 12. Division of Chronic Inflammation and Cancer, German Cancer Research Center, Im Neuenheimer Feld, Heidelberg, Germany
  • 13. Department of Biochemistry and Cell Biology, Max F. Perutz Laboratories, University of Vienna, Vienna, Austria

Description

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.

Notes

This study was supported by the project National Institute for Research of Metabolic and Cardiovascular Diseases (Programme EXCELES, Project No. LX22NPO5104)—Funded by the European Union—Next Generation EU.

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40052672 (PMID)
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2050-084X (ISSN)
References
10.7554/eLife.102205 (DOI)