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.

• Klíčová slova
• cancer biology, cell biology, cytoskeletal crosstalk, hepatocellular carcinoma, metastasis, mouse, plecstatin, plectin, therapeutic strategy,
• MeSH
• cytoskelet * metabolismus   MeSH
• hepatocelulární karcinom * patologie   MeSH
• lidé MeSH
• metastázy nádorů MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory jater * patologie   MeSH
• plektin * metabolismus   genetika   antagonisté a inhibitory   MeSH
• proliferace buněk MeSH
• signální transdukce MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• plektin * MeSH

Epithelia are multicellular sheets that form barriers defining the internal and external environments. The constant stresses acting at this interface require that epithelial sheets are mechanically robust and provide a selective barrier to the hostile exterior. These properties are mediated by cellular junctions which are physically linked with heavily crosslinked cytoskeletal networks. Such hardwiring is facilitated by plakins, a family of giant modular proteins which serve as 'molecular bridges' between different cytoskeletal filaments and multiprotein adhesion complexes. Dysfunction of cytoskeletal crosslinking compromises epithelial biomechanics and structural integrity. Subsequent loss of barrier function leads to disturbed tissue homeostasis and pathological consequences such as skin blistering or intestinal inflammation. In this article, we highlight the importance of the cytolinker protein plectin for the functional organization of epithelial cytoskeletal networks. In particular, we focus on the ability of plectin to act as an integrator of the epithelial cytoarchitecture that defines the biomechanics of the whole tissue. Finally, we also discuss the role of cytoskeletal crosslinking in emerging aspects of epithelial mechanobiology that are critical for the maintenance of epithelial homeostasis.

• Klíčová slova
• cytoskeletal crosstalk, epithelia, mechanobiology, plectin,
• MeSH
• biomechanika MeSH
• cytoskelet * metabolismus   MeSH
• epitelové buňky * metabolismus   cytologie   MeSH
• lidé MeSH
• plektin * metabolismus   chemie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• plektin * MeSH

The coordinated interplay of cytoskeletal networks critically determines tissue biomechanics and structural integrity. Here, we show that plectin, a major intermediate filament-based cytolinker protein, orchestrates cortical cytoskeletal networks in epithelial sheets to support intercellular junctions. By combining CRISPR/Cas9-based gene editing and pharmacological inhibition, we demonstrate that in an F-actin-dependent context, plectin is essential for the formation of the circumferential keratin rim, organization of radial keratin spokes, and desmosomal patterning. In the absence of plectin-mediated cytoskeletal cross-linking, the aberrant keratin-desmosome (DSM)-network feeds back to the actin cytoskeleton, which results in elevated actomyosin contractility. Also, by complementing a predictive mechanical model with Förster resonance energy transfer-based tension sensors, we provide evidence that in the absence of cytoskeletal cross-linking, major intercellular junctions (adherens junctions and DSMs) are under intrinsically generated tensile stress. Defective cytoarchitecture and tensional disequilibrium result in reduced intercellular cohesion, associated with general destabilization of plectin-deficient sheets upon mechanical stress.

• MeSH
• aktiny metabolismus   MeSH
• biomechanika MeSH
• buňky MDCK MeSH
• cytoskelet metabolismus   ultrastruktura   MeSH
• desmozomy metabolismus   ultrastruktura   MeSH
• epitelové buňky metabolismus   ultrastruktura   MeSH
• genový knockout MeSH
• keratiny metabolismus   MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• myši MeSH
• pevnost v tahu MeSH
• plektin metabolismus   MeSH
• protein - isoformy metabolismus   MeSH
• psi MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• psi MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• aktiny MeSH
• keratiny MeSH
• plektin MeSH
• protein - isoformy MeSH