Latest Publications

@article{drapela_pre-existing_2024,

title = {Pre-existing cell subpopulations in primary prostate cancer tumors display surface fingerprints of docetaxel-resistant cells.},

author = {Stanislav Drápela and Barbora Kvokačková and Eva Slabáková and Anna Kotrbová and Kristína Gömöryová and Radek Fedr and Daniela Kurfürstová and Martin Eliáš and Vladimír Jr Študent and Frederika Lenčéšová and Ganji Sri Ranjani and Vendula Pospíchalová and Vítězslav Bryja and Wytske M. Weerden and Martin Puhr and Zoran Culig and Jan Bouchal and Karel Souček},

doi = {10.1007/s13402-024-00982-2},

issn = {2211-3436 2211-3428},

year  = {2024},

date = {2024-08-01},

journal = {Cellular oncology (Dordrecht, Netherlands)},

abstract = {PURPOSE: Docetaxel resistance is a significant obstacle in the treatment of prostate cancer (PCa), resulting in unfavorable patient prognoses. Intratumoral heterogeneity, often associated with epithelial-to-mesenchymal transition (EMT), has previously emerged as a phenomenon that facilitates adaptation to various stimuli, thus promoting cancer cell diversity and eventually resistance to chemotherapy, including docetaxel. Hence, understanding intratumoral heterogeneity is essential for better patient prognosis and the development of personalized treatment strategies. METHODS: To address this, we employed a high-throughput single-cell flow cytometry approach to identify a specific surface fingerprint associated with docetaxel-resistance in PCa cells and complemented it with proteomic analysis of extracellular vesicles. We further validated selected antigens using docetaxel-resistant patient-derived xenografts in vivo and probed primary PCa specimens to interrogate of their surface fingerprint. RESULTS: Our approaches revealed a 6-molecule surface fingerprint linked to docetaxel resistance in primary PCa specimens. We observed consistent overexpression of CD95 (FAS/APO-1), and SSEA-4 surface antigens in both in vitro and in vivo docetaxel-resistant models, which was also observed in a cell subpopulation of primary PCa tumors exhibiting EMT features. Furthermore, CD95, along with the essential enzymes involved in SSEA-4 synthesis, ST3GAL1, and ST3GAL2, displayed a significant increase in patients with PCa undergoing docetaxel-based therapy, correlating with poor survival outcomes. CONCLUSION: In summary, we demonstrate that the identified 6-molecule surface fingerprint associated with docetaxel resistance pre-exists in a subpopulation of primary PCa tumors before docetaxel treatment. Thus, this fingerprint warrants further validation as a promising predictive tool for docetaxel resistance in PCa patients prior to therapy initiation.},

note = {Place: Netherlands},

keywords = {CD95/Fas, Docetaxel resistance, Intratumoral heterogeneity, Plasticity, Prostate cancer, SSEA-4},

pubstate = {published},

tppubtype = {article}

}

@article{culig_editorial_2023,

title = {Editorial: Heterogeneity and plasticity of prostate cancer.},

author = {Zoran Culig and Mohit Kumar Jolly and Karel Souček},

doi = {10.3389/fmolb.2023.1228126},

issn = {2296-889X},

year  = {2023},

date = {2023-01-01},

journal = {Frontiers in molecular biosciences},

volume = {10},

pages = {1228126},

note = {Place: Switzerland},

keywords = {heterogeneity, immunotherapy, oncogenic miRNA, Plasticity, Prostate cancer, therapy resistance, Transcription Factors, tumor-suppressive miRNA},

pubstate = {published},

tppubtype = {article}

}

@article{kvokackova_phenotypic_2021,

title = {Phenotypic Heterogeneity of Triple-Negative Breast Cancer Mediated by Epithelial-Mesenchymal Plasticity.},

author = {Barbora Kvokačková and Ján Remšík and Mohit Kumar Jolly and Karel Souček},

doi = {10.3390/cancers13092188},

issn = {2072-6694},

year  = {2021},

date = {2021-05-01},

journal = {Cancers},

volume = {13},

number = {9},

abstract = {Triple-negative breast cancer (TNBC) is a subtype of breast carcinoma known for its unusually aggressive behavior and poor clinical outcome. Besides the lack of molecular targets for therapy and profound intratumoral heterogeneity, the relatively quick overt metastatic spread remains a major obstacle in effective clinical management. The metastatic colonization of distant sites by primary tumor cells is affected by the microenvironment, epigenetic state of particular subclones, and numerous other factors. One of the most prominent processes contributing to the intratumoral heterogeneity is an epithelial-mesenchymal transition (EMT), an evolutionarily conserved developmental program frequently hijacked by tumor cells, strengthening their motile and invasive features. In response to various intrinsic and extrinsic stimuli, malignant cells can revert the EMT state through the mesenchymal-epithelial transition (MET), a process that is believed to be critical for the establishment of macrometastasis at secondary sites. Notably, cancer cells rarely undergo complete EMT and rather exist in a continuum of E/M intermediate states, preserving high levels of plasticity, as demonstrated in primary tumors and, ultimately, in circulating tumor cells, representing a simplified element of the metastatic cascade. In this review, we focus on cellular drivers underlying EMT/MET phenotypic plasticity and its detrimental consequences in the context of TNBC cancer.},

note = {Place: Switzerland},

keywords = {epithelial–mesenchymal transition, mesenchymal–epithelial transition, Metastasis, Plasticity, triple-negative breast cancer},

pubstate = {published},

tppubtype = {article}

}

@article{drapela_zeb1_2020,

title = {ZEB1: A Critical Regulator of Cell Plasticity, DNA Damage Response, and Therapy Resistance.},

author = {Stanislav Drápela and Jan Bouchal and Mohit Kumar Jolly and Zoran Culig and Karel Souček},

doi = {10.3389/fmolb.2020.00036},

issn = {2296-889X},

year  = {2020},

date = {2020-01-01},

journal = {Frontiers in molecular biosciences},

volume = {7},

pages = {36},

abstract = {The predominant way in which conventional chemotherapy kills rapidly proliferating cancer cells is the induction of DNA damage. However, chemoresistance remains the main obstacle to therapy effectivity. An increasing number of studies suggest that epithelial-to-mesenchymal transition (EMT) represents a critical process affecting the sensitivity of cancer cells to chemotherapy. Zinc finger E-box binding homeobox 1 (ZEB1) is a prime element of a network of transcription factors controlling EMT and has been identified as an important molecule in the regulation of DNA damage, cancer cell differentiation, and metastasis. Recent studies have considered upregulation of ZEB1 as a potential modulator of chemoresistance. It has been hypothesized that cancer cells undergoing EMT acquire unique properties that resemble those of cancer stem cells (CSCs). These stem-like cells manifest enhanced DNA damage response (DDR) and DNA repair capacity, self-renewal, or chemoresistance. In contrast, functional experiments have shown that ZEB1 induces chemoresistance regardless of whether other EMT-related changes occur. ZEB1 has also been identified as an important regulator of DDR by the formation of a ZEB1/p300/PCAF complex and direct interaction with ATM kinase, which has been linked to radioresistance. Moreover, ATM can directly phosphorylate ZEB1 and enhance its stability. Downregulation of ZEB1 has also been shown to reduce the abundance of CHK1, an effector kinase of DDR activated by ATR, and to induce its ubiquitin-dependent degradation. In this perspective, we focus on the role of ZEB1 in the regulation of DDR and describe the mechanisms of ZEB1-dependent chemoresistance.},

note = {Place: Switzerland},

keywords = {DNA damage response, EMT-epithelial to mesenchymal transition, Plasticity, therapy resistance, ZEB1},

pubstate = {published},

tppubtype = {article}

}