Metastatic melanoma, a highly lethal form of skin cancer, presents significant clinical challenges due to limited therapeutic options and high metastatic capacity. Recent studies have demonstrated that cancer dissemination can occur earlier, before the diagnosis of the primary tumor. The progress in understanding the kinetics of cancer dissemination is limited by the lack of animal models that accurately mimic disease progression. We have established a xenograft model of human melanoma that spontaneously metastasizes to lymph nodes and lungs. This model allows precise monitoring of melanoma progression and is suitable for the quantitative and qualitative analysis of circulating tumor cells (CTCs). We have validated a flow cytometry-based protocol for CTCs enumeration and isolation. We could demonstrate that (i) CTCs were detectable in the bloodstream from the fourth week after tumor initiation, coinciding with the lymph node metastases appearance, (ii) excision of the primary tumor accelerated the formation of metastases in lymph nodes and lungs as early as one-week post-surgery, accompanied by the increased numbers of CTCs, and (iii) CTCs change their surface protein signature. In summary, we present a model of human melanoma that can be effectively utilized for future drug efficacy studies.

• Klíčová slova
• Circulating tumor cells, In vivo model, Melanoma, Metastasis, Tumorectomy,
• MeSH
• lidé MeSH
• lymfatické metastázy MeSH
• melanom * patologie   MeSH
• nádorové cirkulující buňky * patologie   MeSH
• nádory kůže * patologie   MeSH
• průtoková cytometrie MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

In cancer, the activating transcription factor 2 (ATF2) has pleiotropic functions in cellular responses to growth stimuli, damage, or inflammation. Due to only limited studies, the significance of ATF2 in colorectal cancer (CRC) is not well understood. We report that low ATF2 levels correlated with worse prognosis and tumor aggressiveness in CRC patients. NanoString gene expression and ChIP analysis confirmed trophoblast cell surface antigen 2 (TROP2) as a novel inhibitory ATF2 target gene. This inverse correlation was further observed in primary human tumor tissues. Immunostainings revealed that high intratumoral heterogeneity for ATF2 and TROP2 expression was sustained also in liver metastasis. Mechanistically, our in vitro data of CRISPR/Cas9-generated ATF2 knockout (KO) clones revealed that high TROP2 levels were critical for cell de-adhesion and increased cell migration without triggering EMT. TROP2 was enriched in filopodia and displaced Paxillin from adherens junctions. In vivo imaging, micro-computer tomography, and immunostainings verified that an ATF2KO/TROP2high status triggered tumor invasiveness in in vivo mouse and chicken xenograft models. In silico analysis provided direct support that ATF2low/TROP2high expression status defined high-risk CRC patients. Finally, our data demonstrate that ATF2 acts as a tumor suppressor by inhibiting the cancer driver TROP2. Therapeutic TROP2 targeting might prevent particularly the first steps in metastasis, i.e., the de-adhesion and invasion of colon cancer cells.

• Klíčová slova
• CAM model, De-adhesion, EMT, Intratumoral heterogeneity, Liver metastasis, Migration,
• MeSH
• antigeny nádorové * genetika   metabolismus   MeSH
• kolorektální nádory * genetika   patologie   MeSH
• lidé MeSH
• molekuly buněčné adheze genetika   metabolismus   MeSH
• myši MeSH
• nádorové buněčné linie metabolismus   MeSH
• proliferace buněk MeSH
• transkripční faktor ATF2 * genetika   metabolismus   MeSH
• upregulace MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigeny nádorové * MeSH
• ATF2 protein, human MeSH Prohlížeč
• molekuly buněčné adheze MeSH
• TACSTD2 protein, human MeSH Prohlížeč
• transkripční faktor ATF2 * MeSH

TACSTD2 encodes a transmembrane glycoprotein Trop2 commonly overexpressed in carcinomas. While the Trop2 protein was discovered already in 1981 and first antibody-drug conjugate targeting Trop2 were recently approved for cancer therapy, the physiological role of Trop2 is still not fully understood. In this article, we show that TACSTD2/Trop2 expression is evolutionarily conserved in lungs of various vertebrates. By analysis of publicly available transcriptomic data we demonstrate that TACSTD2 level consistently increases in lungs infected with miscellaneous, but mainly viral pathogens. Single cell and subpopulation based transcriptomic data revealed that the major source of TACSTD2 transcript are lung epithelial cells and their progenitors and that TACSTD2 is induced directly in lung epithelial cells following infection. Increase in TACSTD2 expression may represent a mechanism to maintain/restore epithelial barrier function and contribute to regeneration process in infected/damaged lungs.

• MeSH
• antigeny nádorové * metabolismus   MeSH
• epitelové buňky metabolismus   MeSH
• molekuly buněčné adheze * metabolismus   MeSH
• plíce metabolismus   MeSH
• upregulace MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigeny nádorové * MeSH
• molekuly buněčné adheze * MeSH

Prostate cancer (PCa) is the second leading cause of cancer-related deaths in men in Western countries, and there is still an urgent need for a better understanding of PCa progression to inspire new treatment strategies. Skp2 is a substrate-recruiting component of the E3 ubiquitin ligase complex, whose activity is regulated through neddylation. Slug is a transcriptional repressor involved in the epithelial-to-mesenchymal transition, which may contribute to therapy resistance. Although Skp2 has previously been associated with a mesenchymal phenotype and prostate cancer progression, the relationship with Slug deserves further elucidation. We have previously shown that a high Gleason score (≥8) is associated with higher Skp2 and lower E-cadherin expression. In this study, significantly increased expression of Skp2, AR, and Slug, along with E-cadherin downregulation, was observed in primary prostate cancer in patients who already had lymph node metastases. Skp2 was slightly correlated with Slug and AR in the whole cohort (Rs 0.32 and 0.37, respectively), which was enhanced for both proteins in patients with high Gleason scores (Rs 0.56 and 0.53, respectively) and, in the case of Slug, also in patients with metastasis to lymph nodes (Rs 0.56). Coexpression of Skp2 and Slug was confirmed in prostate cancer tissues by multiplex immunohistochemistry and confocal microscopy. The same relationship between these two proteins was observed in three sets of prostate epithelial cell lines (PC3, DU145, and E2) and their mesenchymal counterparts. Chemical inhibition of Skp2, but not RNA interference, modestly decreased Slug protein in PC3 and its docetaxel-resistant subline PC3 DR12. Importantly, chemical inhibition of Skp2 by MLN4924 upregulated p27 and decreased Slug expression in PC3, PC3 DR12, and LAPC4 cells. Novel treatment strategies targeting Skp2 and Slug by the neddylation blockade may be promising in advanced prostate cancer, as recently documented for other aggressive solid tumors.

• Klíčová slova
• Skp2 (S-phase kinase-associated protein 2), Slug, immunohistochemistry, multiplex, neddylation, prostate cancer,
• MeSH
• androgenní receptory genetika   metabolismus   MeSH
• buňky PC-3 MeSH
• CD antigeny genetika   metabolismus   MeSH
• cyklopentany farmakologie   MeSH
• docetaxel farmakologie   MeSH
• epitelo-mezenchymální tranzice genetika   MeSH
• inhibitor p27 cyklin-dependentní kinasy genetika   metabolismus   MeSH
• kadheriny genetika   metabolismus   MeSH
• lidé MeSH
• lymfatické metastázy MeSH
• malá interferující RNA genetika   metabolismus   MeSH
• nádorové buněčné linie MeSH
• nádory prostaty genetika   metabolismus   patologie   MeSH
• posttranslační úpravy proteinů * MeSH
• prostata metabolismus   patologie   MeSH
• protein NEDD8 genetika   metabolismus   MeSH
• proteiny asociované s kinázou S-fáze antagonisté a inhibitory   genetika   metabolismus   MeSH
• protinádorové látky farmakologie   MeSH
• pyrimidiny farmakologie   MeSH
• regulace genové exprese u nádorů MeSH
• rodina transkripčních faktorů Snail genetika   metabolismus   MeSH
• stupeň nádoru MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• androgenní receptory MeSH
• CD antigeny MeSH
• CDH1 protein, human MeSH Prohlížeč
• cyklopentany MeSH
• docetaxel MeSH
• inhibitor p27 cyklin-dependentní kinasy MeSH
• kadheriny MeSH
• malá interferující RNA MeSH
• NEDD8 protein, human MeSH Prohlížeč
• pevonedistat MeSH Prohlížeč
• protein NEDD8 MeSH
• proteiny asociované s kinázou S-fáze MeSH
• protinádorové látky MeSH
• pyrimidiny MeSH
• rodina transkripčních faktorů Snail MeSH
• SKP2 protein, human MeSH Prohlížeč
• SNAI1 protein, human MeSH Prohlížeč

Trophoblast cell surface antigen 2 (Trop2) is a widely expressed glycoprotein and an epithelial cell adhesion molecule (EpCAM) family member. Although initially identified as a transmembrane protein, other subcellular localizations and processed forms were described. Its congenital mutations cause a gelatinous drop-like corneal dystrophy, a disease characterized by loss of barrier function in corneal epithelial cells. Trop2 is considered a stem cell marker and its expression associates with regenerative capacity in various tissues. Trop2 overexpression was described in tumors of different origins; however, functional studies revealed both oncogenic and tumor suppressor roles. Nevertheless, therapeutic potential of Trop2 was recognized and clinical studies with drug-antibody conjugates have been initiated in various cancer types. One of these agents, sacituzumab govitecan, has been recently granted an accelerated approval for therapy of metastatic triple-negative breast cancer. In this article, we review the current knowledge about the yet controversial function of Trop2 in homeostasis and pathology.

• Klíčová slova
• TACSTD2, Trop2, cancer, epithelial-to-mesenchymal transition, metastases, proliferation, therapy,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Skp2 is a crucial component of SCFSkp2 E3 ubiquitin ligase and is often overexpressed in various types of cancer, including prostate cancer (PCa). The epithelial-to-mesenchymal transition (EMT) is involved in PCa progression. The acquisition of a mesenchymal phenotype that results in a cancer stem cell (CSC) phenotype in PCa was described. Therefore, we aimed to investigate the expression and localization of Skp2 in clinical samples from patients with PCa, the association of Skp2 with EMT status, and the role of Skp2 in prostate CSC. We found that nuclear expression of Skp2 was increased in patients with PCa compared to those with benign hyperplasia, and correlated with high Gleason score in PCa patients. Increased Skp2 expression was observed in PCa cell lines with mesenchymal and CSC-like phenotype compared to their epithelial counterparts. Conversely, the CSC-like phenotype was diminished in cells in which SKP2 expression was silenced. Furthermore, we observed that Skp2 downregulation led to the decrease in subpopulation of CD44+CD24- cancer stem-like cells. Finally, we showed that high expression levels of both CD24 and CD44 were associated with favorable recurrence-free survival for PCa patients. This study uncovered the Skp2-mediated CSC-like phenotype with oncogenic functions in PCa.

• MeSH
• antigen CD24 genetika   MeSH
• antigeny CD44 genetika   MeSH
• buňky PC-3 MeSH
• epitelo-mezenchymální tranzice * MeSH
• lidé MeSH
• myši nahé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádorové kmenové buňky metabolismus   fyziologie   MeSH
• nádory prostaty genetika   metabolismus   patofyziologie   MeSH
• proteiny asociované s kinázou S-fáze genetika   MeSH
• regulace genové exprese u nádorů * MeSH
• stupeň nádoru MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigen CD24 MeSH
• antigeny CD44 MeSH
• CD24 protein, human MeSH Prohlížeč
• CD44 protein, human MeSH Prohlížeč
• proteiny asociované s kinázou S-fáze MeSH
• SKP2 protein, human MeSH Prohlížeč