Outla Zuzana, Oyman-Eyrilmez Gizem, Korelova Katerina, Prechova Magdalena, Frick Lukas, Sarnova Lenka, Bisht Piyush, Novotna Petra, Kosla Jan, Bortel Patricia, Borutzki Yasmin, Bileck Andrea, Gerner Christopher, Rahbari Mohammad, Rahbari Nuh, Birgin Emrullah, Kvasnicova Bibiana, Galisova Andrea, Sulkova Katerina, Bauer Andreas, Jobe Njainday, Tolde Ondrej, Sticova Eva, Rösel Daniel, O'Connor Tracy, Otahal Martin, Jirak Daniel, Heikenwälder Mathias, Wiche Gerhard, Meier-Menches Samuel M, Gregor Martin
Laboratory of Integrative Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic.
Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland.
Elife. 2025 Mar 7;13:RP102205. doi: 10.7554/eLife.102205.
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.
最常见的原发性肝癌——肝细胞癌（HCC），是一种具有高转移潜能和复杂病理生理学的异质性肿瘤实体。越来越多的证据表明，组织力学在肿瘤的发生和发展中起着关键作用。在此，我们表明，网蛋白（一种主要的细胞骨架交联蛋白）在机械稳态和驱动肝癌发生的机械敏感致癌信号传导中起着至关重要的作用。我们的表达分析显示，肝肿瘤中网蛋白水平升高，这与HCC患者的不良预后相关。利用原位和异位小鼠模型，我们证明了网蛋白的基因和药理学失活可有效抑制HCC的起始和生长。此外，靶向网蛋白可有效抑制人HCC细胞的侵袭潜能，并减少其在肺中的转移生长。蛋白质组学和磷酸化蛋白质组学分析将网蛋白依赖性细胞骨架网络破坏与致癌性粘着斑激酶（FAK）、丝裂原活化蛋白激酶/细胞外信号调节激酶（MAPK/Erk）和磷脂酰肌醇-3-激酶/蛋白激酶B（PI3K/Akt）信号的减弱联系起来。重要的是，通过结合基于细胞系和小鼠HCC模型，我们表明网蛋白抑制剂网抑素-1（PST）耐受性良好，并能有效抑制HCC进展。总之，我们的研究表明，网蛋白控制的细胞结构是HCC发展的关键决定因素，并表明药理学诱导的机械稳态破坏可能代表一种新的HCC治疗策略。
