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.

• Keywords
• cancer biology, cell biology, cytoskeletal crosstalk, hepatocellular carcinoma, metastasis, mouse, plecstatin, plectin, therapeutic strategy,
• MeSH
• Cytoskeleton * metabolism   MeSH
• Carcinoma, Hepatocellular * pathology   MeSH
• Humans MeSH
• Neoplasm Metastasis MeSH
• Disease Models, Animal MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Liver Neoplasms * pathology   MeSH
• Plectin * metabolism   genetics   antagonists & inhibitors   MeSH
• Cell Proliferation MeSH
• Signal Transduction MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Plectin * 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.

• Keywords
• cytoskeletal crosstalk, epithelia, mechanobiology, plectin,
• MeSH
• Biomechanical Phenomena MeSH
• Cytoskeleton * metabolism   MeSH
• Epithelial Cells * metabolism   cytology   MeSH
• Humans MeSH
• Plectin * metabolism   chemistry   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Plectin * MeSH

Herein, we report a series of new octahedral iridium(III) complexes Ir1-Ir9 of the type [Ir(N^N^N)(C^N)Cl]PF6 (N^N^N = 4'-(p-tolyl)-2,2':6',2″-terpyridine; C^N = deprotonated 2-arylbenzimidazole backbone) to introduce new metal-based compounds for effective inhibition of metastatic processes in triple-negative breast cancer (TNBC). The results show that the structural modifications within the C^N scaffold strongly impact the antimetastatic properties of these complexes in TNBC cells. Furthermore, testing the antimetastatic effects of the investigated Ir complexes revealed that the highest antimetastatic activity in TNBC cells is exhibited by complex Ir1. This result was in contrast to the effects of the clinically used drug doxorubicin used in conventional chemotherapy of TNBC, which conversely promoted metastatic properties of TNBC cells. Thus, the latter result suggests that doxorubicin chemotherapy may increase the risk of metastasis of breast cancer cells, so the search for new drugs to treat breast cancer that would show better antitumor effects than doxorubicin is justified.

• MeSH
• Doxorubicin pharmacology   therapeutic use   MeSH
• Humans MeSH
• Ligands MeSH
• Cell Line, Tumor MeSH
• Cell Proliferation MeSH
• Antineoplastic Agents * chemistry   MeSH
• Triple Negative Breast Neoplasms * drug therapy   pathology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Doxorubicin MeSH
• Ligands MeSH
• Antineoplastic Agents * MeSH

The ability of cells to switch between different invasive modes during metastasis, also known as invasion plasticity, is an important characteristic of tumor cells that makes them able to resist treatment targeted to a particular invasion mode. Due to the rapid changes in cell morphology during the transition between mesenchymal and amoeboid invasion, it is evident that this process requires remodeling of the cytoskeleton. Although the role of the actin cytoskeleton in cell invasion and plasticity is already quite well described, the contribution of microtubules is not yet fully clarified. It is not easy to infer whether destabilization of microtubules leads to higher invasiveness or the opposite since the complex microtubular network acts differently in diverse invasive modes. While mesenchymal migration typically requires microtubules at the leading edge of migrating cells to stabilize protrusions and form adhesive structures, amoeboid invasion is possible even in the absence of long, stable microtubules, albeit there are also cases of amoeboid cells where microtubules contribute to effective migration. Moreover, complex crosstalk of microtubules with other cytoskeletal networks participates in invasion regulation. Altogether, microtubules play an important role in tumor cell plasticity and can be therefore targeted to affect not only cell proliferation but also invasive properties of migrating cells.

• Keywords
• 3D migration, amoeboid, cancer, invasion plasticity, mesenchymal, microtubules,
• Publication type
• Journal Article MeSH
• Review MeSH

Trophoblastic cell surface antigen 2 (TROP2) is a membrane glycoprotein overexpressed in many solid tumors with a poor prognosis, including intestinal neoplasms. In our study, we show that TROP2 is expressed in preneoplastic lesions, and its expression is maintained in most colorectal cancers (CRC). High TROP2 positivity correlated with lymph node metastases and poor tumor differentiation and was a negative prognostic factor. To investigate the role of TROP2 in intestinal tumors, we analyzed two mouse models with conditional disruption of the adenomatous polyposis coli (Apc) tumor-suppressor gene, human adenocarcinoma samples, patient-derived organoids, and TROP2-deficient tumor cells. We found that Trop2 is produced early after Apc inactivation and its expression is associated with the transcription of genes involved in epithelial-mesenchymal transition, the regulation of migration, invasiveness, and extracellular matrix remodeling. A functionally similar group of genes was also enriched in TROP2-positive cells from human CRC samples. To decipher the driving mechanism of TROP2 expression, we analyzed its promoter. In human cells, this promoter was activated by β-catenin and additionally by the Yes1-associated transcriptional regulator (YAP). The regulation of TROP2 expression by active YAP was verified by YAP knockdown in CRC cells. Our results suggest a possible link between aberrantly activated Wnt/β-catenin signaling, YAP, and TROP2 expression.

• Keywords
• APC, EMT, TACSTD2, WNT/β-catenin signaling, colorectal cancer, expression profiling, organoids,
• Publication type
• Journal Article MeSH

The knowledge of the structure, function, and abundance of specific proteins related to the EMT process is essential for developing effective diagnostic approaches to cancer with the perspective of diagnosis and therapy of malignancies. The success of all-trans retinoic acid (ATRA) differentiation therapy in acute promyelocytic leukemia has stimulated studies in the treatment of other tumors with ATRA. This review will discuss the impact of ATRA use, emphasizing epithelial-mesenchymal transition (EMT) proteins in breast cancer, of which metastasis and recurrence are major causes of death.

• Keywords
• ATRA, EMT, breast cancer, protein,
• MeSH
• Epithelial-Mesenchymal Transition * MeSH
• Humans MeSH
• Neoplasm Metastasis MeSH
• Neoplasm Proteins agonists   metabolism   MeSH
• Breast Neoplasms metabolism   mortality   pathology   MeSH
• Receptors, Retinoic Acid agonists   metabolism   MeSH
• Tretinoin metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Neoplasm Proteins MeSH
• Receptors, Retinoic Acid MeSH
• Tretinoin MeSH