Biology subjects

Kucerova, L.

Publications and source records attributed to Kucerova, L..

4 recordsLinked to original sources

bioRxiv2025

Development of Paclitaxel Resistance in Triple-Negative Breast Cancer Is Associated with Extensive DNA Methylation Changes That Are Partially Reversed by Decitabine

AimsChemotherapy resistance remains a major challenge in breast cancer (BC) treatment. This study investigated whether resistance development is associated with DNA methylation changes and assessed the potential of the DNA methyltransferase inhibitor decitabine (DAC) to reverse these alterations and enhance chemosensitivity. MethodsMolecular profiling and functional assays were used to characterize paclitaxel-(PAC) and doxorubicin-(DOX) resistant BC cell lines derived from luminal A (T-47D), triple-negative (MDA-MB-231), and HER2-positive trastuzumab-resistant (JIMT-1) models. Therapeutic responses to DAC and DOX, alone and in combination, were evaluated in MDA-MB-231 xenografts. DNA methylation-associated gene expression changes were analyzed through integrative approaches. ResultsChemoresistant cells exhibited a slow-cycling phenotype, reduced tumorigenicity, and extensive genomic alterations. Upregulation of RELB and downregulation of PPARG were observed across several resistant cell lines, while CDA expression was uniformly elevated in all DOX-resistant models. PAC-resistant xenografts displayed widespread methylation and transcriptomic reprogramming. DAC treatment partially restored aberrant methylation patterns and increased Ki-67 expression, potentially enhancing DOX responsiveness. ConclusionsChemoresistance in BC involves extensive genomic and epigenetic reprogramming. DAC modulates methylation and tumor phenotype but is insufficient to overcome resistance, highlighting the need for rational combination strategies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/655519v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@8c6b06org.highwire.dtl.DTLVardef@c67805org.highwire.dtl.DTLVardef@1f1b282org.highwire.dtl.DTLVardef@feb046_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2021

RNF43 inhibits WNT5A driven signaling and suppresses melanoma invasion

RNF43 is a E3 ubiquitin ligase and known negative regulator of WNT/{beta}-catenin signaling. We demonstrate that RNF43 is also 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. This activity of RNF43 is physiologically relevant and blocks 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 inhibitor. In line with these findings, RNF43 expression decreases during melanoma progression and RNF43-low patients have worse prognosis. We conclude that RNF43 is a newly discovered negative regulator of WNT5A-mediated biological responses that desensitizes cells to WNT5A.

cancer biology↗

bioRxiv2019

Adenosine receptor and its downstream target mod(mdg4) modify the pathogenic effects of polyglutamine in a Drosophila model of Huntington's disease

Adenosine (Ado) is an important signaling molecule involved in stress responses. Studies in mammalian models have shown that Ado regulates signaling mechanisms involved in danger-sensing and tissue-protection. Yet, little is known about the role of Ado signaling in Drosophila. In the present study, we observed lower extracellular Ado concentration and suppressed expression of Ado transporters in flies expressing mutant huntingtin protein (mHTT). We altered Ado signaling using genetic tools and found that the overexpression of Ado metabolic enzymes, as well as the suppression of Ado receptor (AdoR) and transporters (ENTs), were able to minimize mHTT-induced mortality. We also identified the downstream targets of the AdoR pathway, the modifier of mdg4 (Mod(mdg4)) and heat-shock protein 70 (Hsp70), which carry out its function. Finally, we showed that a decrease in Ado signaling affect other Drosophila stress reactions, including paraquat and heat-shock treatments. Our study provides important insights into how Ado regulates stress responses in Drosophila.

genetics↗

bioRxiv2019

The consequences of surviving infection across the metamorphic boundary: tradeoff insights from RNAseq and life history measures

The broad diversity of insect life has been shaped, in part, by pathogen pressure, yet the influence of injury and infection during critical periods of development is understudied. During development, insects undergo metamorphosis, wherein the organism experiences a dramatic shift in their overall morphology, and physiology. In temperate zones, metamorphosis is often directly followed by a developmental arrest called diapause, for which the insect needs to acquire enough energy reserves before the onset of winter. We investigated the long-term effects of injury and infection using two bacteria in the butterfly Pieris napi, revealing that the negative consequences of bacterial infection carry across the metamorphic boundary. Initial direct effects of infection were weight loss and slower development, as well as an increased mortality at higher infection levels. The detrimental effects were stronger in the gram-positive Micrococcus luteus compared to gram-negative Escherichia coli. Transcriptome-wide differences between the two bacteria were already observed in the gene expression profile of the first 24 hours after infection. Larvae infected with M. luteus showed a strong suppression of all non-immunity related processes, with several types of immune responses being activated. The impact of these transcriptomic changes, a tradeoff between homeostasis and immune response, were visible in the life history data, wherein individuals infected with M. luteus had the highest mortality rate, along with the lowest pupal weight, developmental rate and adult weight of all the treatments. Overall, we find that the cost of infection and wounding in the final larval instar carries over the metamorphic boundary, and is expected to negatively affect their lifetime fitness.

evolutionary biology↗