Latest Publications

@article{valcikova_eif4f_2024,

title = {eIF4F controls ERK MAPK signaling in melanomas with BRAF and NRAS mutations.},

author = {Barbora Valcikova and Natalia Vadovicova and Karolina Smolkova and Magdalena Zacpalova and Pavel Krejci and Shannon Lee and Jens Rauch and Walter Kolch and Alexander Kriegsheim and Anna Dorotikova and Zdenek Andrysik and Rachel Vichova and Ondrej Vacek and Karel Soucek and Stjepan Uldrijan},

doi = {10.1073/pnas.2321305121},

issn = {1091-6490 0027-8424},

year  = {2024},

date = {2024-10-01},

journal = {Proceedings of the National Academy of Sciences of the United States of America},

volume = {121},

number = {44},

pages = {e2321305121},

abstract = {The eIF4F translation initiation complex plays a critical role in melanoma resistance to clinical BRAF and MEK inhibitors. In this study, we uncover a function of eIF4F in the negative regulation of the rat sarcoma (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) signaling pathway. We demonstrate that eIF4F is essential for controlling ERK signaling intensity in treatment-naïve melanoma cells harboring BRAF or NRAS mutations. Specifically, the dual-specificity phosphatase DUSP6/MKP3, which acts as a negative feedback regulator of ERK activity, requires continuous production in an eIF4F-dependent manner to limit excessive ERK signaling driven by oncogenic RAF/RAS mutations. Treatment with small-molecule eIF4F inhibitors disrupts the negative feedback control of MAPK signaling, leading to ERK hyperactivation and EGR1 overexpression in melanoma cells in vitro and in vivo. Furthermore, our quantitative analyses reveal a high spare signaling capacity in the ERK pathway, suggesting that eIF4F-dependent feedback keeps the majority of ERK molecules inactive under normal conditions. Overall, our findings highlight the crucial role of eIF4F in regulating ERK signaling flux and suggest that pharmacological eIF4F inhibitors can disrupt the negative feedback control of MAPK activity in melanomas with BRAF and NRAS activating mutations.},

note = {Place: United States},

keywords = {*Eukaryotic Initiation Factor-4F/metabolism/genetics, *GTP Phosphohydrolases/metabolism/genetics, *MAP Kinase Signaling System/genetics, *Melanoma/genetics/metabolism/pathology, *Membrane Proteins/metabolism/genetics, *Mutation, *Proto-Oncogene Proteins B-raf/genetics/metabolism, Animals, Cell Line, Dual Specificity Phosphatase 6/metabolism/genetics, DUSP6, eIF4F, ERK, Extracellular Signal-Regulated MAP Kinases/metabolism, Humans, MAP kinase, Melanoma, Mice, Tumor},

pubstate = {published},

tppubtype = {article}

}

@article{pickova_orthotopic_2024,

title = {Orthotopic model for the analysis of melanoma circulating tumor cells.},

author = {Markéta Pícková and Zuzana Kahounová and Tomasz Radaszkiewicz and Jiřina Procházková and Radek Fedr and Michaela Nosková and Katarzyna Anna Radaszkiewicz and Petra Ovesná and Vítězslav Bryja and Karel Souček},

doi = {10.1038/s41598-024-58236-y},

issn = {2045-2322},

year  = {2024},

date = {2024-04-01},

journal = {Scientific reports},

volume = {14},

number = {1},

pages = {7827},

abstract = {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.},

note = {Place: England},

keywords = {*Melanoma/pathology, *Neoplastic Cells, *Skin Neoplasms/pathology, Animals, Circulating tumor cells, Circulating/pathology, Flow Cytometry, Humans, In vivo model, Lymphatic Metastasis, Melanoma, Metastasis, Tumorectomy},

pubstate = {published},

tppubtype = {article}

}

@article{radaszkiewicz_rnf43_2021,

title = {RNF43 inhibits WNT5A-driven signaling and suppresses melanoma invasion and resistance to the targeted therapy.},

author = {Tomasz Radaszkiewicz and Michaela Nosková and Kristína Gömöryová and Olga Vondálová Blanářová and Katarzyna Anna Radaszkiewicz and Markéta Picková and Ráchel Víchová and Tomáš Gybeľ and Karol Kaiser and Lucia Demková and Lucia Kučerová and Tomáš Bárta and David Potěšil and Zbyněk Zdráhal and Karel Souček and Vítězslav Bryja},

doi = {10.7554/eLife.65759},

issn = {2050-084X},

year  = {2021},

date = {2021-10-01},

journal = {eLife},

volume = {10},

abstract = {RNF43 is an E3 ubiquitin ligase and known negative regulator of WNT/β-catenin signaling. We demonstrate that RNF43 is also a regulator of noncanonical WNT5A-induced signaling in human cells. Analysis of the RNF43 interactome using BioID and immunoprecipitation showed that RNF43 can interact with the core receptor complex components dedicated to the noncanonical Wnt pathway such as ROR1, ROR2, VANGL1, and VANGL2. RNF43 triggers VANGL2 ubiquitination and proteasomal degradation and clathrin-dependent internalization of ROR1 receptor and inhibits ROR2 activation. These activities of RNF43 are physiologically relevant and block pro-metastatic WNT5A signaling in melanoma. RNF43 inhibits responses to WNT5A, which results in the suppression of invasive properties of melanoma cells. Furthermore, RNF43 prevented WNT5A-assisted development of resistance to BRAF V600E and MEK inhibitors. Next, RNF43 acted as melanoma suppressor and improved response to targeted therapies in vivo. In line with these findings, RNF43 expression decreases during melanoma progression and RNF43-low patients have a worse prognosis. We conclude that RNF43 is a newly discovered negative regulator of WNT5A-mediated biological responses that desensitizes cells to WNT5A.},

note = {Place: England},

keywords = {*Melanoma/genetics/pathology/prevention & control, *Signal Transduction, Animals, BRAF V600E, cancer biology, cell biology, human, Inbred NOD, Male, Melanoma, Mice, mouse, Neoplasm Invasiveness/genetics, RNF43, ROR1, Ubiquitin-Protein Ligases/*genetics/metabolism, VANGL1, Wnt-5a Protein/*genetics/metabolism, WNT5A},

pubstate = {published},

tppubtype = {article}

}

@article{verlande_metabolic_2018,

title = {Metabolic stress regulates ERK activity by controlling KSR-RAF heterodimerization.},

author = {Amandine Verlande and Michaela Krafčíková and David Potěšil and Lukáš Trantírek and Zbyněk Zdráhal and Moustafa Elkalaf and Jan Trnka and Karel Souček and Nora Rauch and Jens Rauch and Walter Kolch and Stjepan Uldrijan},

doi = {10.15252/embr.201744524},

issn = {1469-3178 1469-221X},

year  = {2018},

date = {2018-02-01},

journal = {EMBO reports},

volume = {19},

number = {2},

pages = {320–336},

abstract = {Altered cell metabolism is a hallmark of cancer, and targeting specific metabolic nodes is considered an attractive strategy for cancer therapy. In this study, we evaluate the effects of metabolic stressors on the deregulated ERK pathway in melanoma cells bearing activating mutations of the NRAS or BRAF oncogenes. We report that metabolic stressors promote the dimerization of KSR proteins with CRAF in NRAS-mutant cells, and with oncogenic BRAF in BRAF(V600E)-mutant cells, thereby enhancing ERK pathway activation. Despite this similarity, the two genomic subtypes react differently when a higher level of metabolic stress is induced. In NRAS-mutant cells, the ERK pathway is even more stimulated, while it is strongly downregulated in BRAF(V600E)-mutant cells. We demonstrate that this is caused by the dissociation of mutant BRAF from KSR and is mediated by activated AMPK. Both types of ERK regulation nevertheless lead to cell cycle arrest. Besides studying the effects of the metabolic stressors on ERK pathway activity, we also present data suggesting that for efficient therapies of both genomic melanoma subtypes, specific metabolic targeting is necessary.},

note = {Place: England},

keywords = {*Protein Multimerization, *Stress, 14-3-3 Proteins/chemistry/metabolism, cell cycle arrest, Cell Cycle Checkpoints/genetics, Cell Line, Cell Survival, Enzyme Activation, Extracellular Signal-Regulated MAP Kinases/*metabolism, Glucose/metabolism, Glycolysis, GTP Phosphohydrolases/genetics/metabolism, Humans, Melanoma, Melanoma/genetics/metabolism, Membrane Proteins/genetics/metabolism, metabolic stress, Mutation, Oxygen Consumption, Physiological, Protein Kinases/chemistry/genetics/*metabolism, raf Kinases/chemistry/genetics/*metabolism, RAF‐ERK signaling, Recombinant Fusion Proteins, Tumor},

pubstate = {published},

tppubtype = {article}

}