Biology subjects

Pospisilova, S.

Publications and source records attributed to Pospisilova, S..

7 recordsLinked to original sources

bioRxiv2026

Retrotransposon Activity in Chronic Lymphocytic Leukemia: Associations with RNA Splicing and TP53 Dysfunction

Retroelements (RE), particularly autonomous Long Interspersed Element-1 (LINE-1), function as potent drivers of genomic instability in various malignancies. While normally silenced by epigenetic mechanisms, their reactivation in cancer cells can drive tumor evolution. TP53 is known to repress LINE-1 transcription; however, the consequences of TP53 dysfunction on retrotransposition and transcriptional activity in chronic lymphocytic leukemia (CLL) remain unknown. To investigate the relationship between TP53 status, LINE-1 retrotranspositional potential, and transcriptomic alterations, we utilized a multi-omics approach, combining a highly sensitive NGS protocol for detecting novel LINE-1 insertions with transcriptomic profiling of transposable elements and protein-coding genes. We applied these methods to a cohort of CLL patients stratified by the presence or absence of TP53 clonal evolution and to CLL-derived cell lines MEC1 and HG3, including CRISPR/Cas9-engineered TP53 mutants. Genomic analysis revealed no evidence of widespread somatic retrotransposition, suggesting that CLL exhibits resistance against de novo LINE-1 insertions. Conversely, transcriptomic profiling uncovered distinct transposon expression signatures aligned with patterns of TP53 mutation status evolution. Notably, differentially expressed genes were significantly enriched in the RNA splicing pathway, indicating that while LINE-1 elements remain largely constrained at the genomic level, their transcriptomic activity may influence cellular rewiring, affecting patterns of TP53 mutation clonal evolution. Based on these results, we argue that the pathogenic contribution of retroelements in CLL lies in transcriptomic dysregulation and splicing alterations, rather than in direct DNA damage caused by LINE-1 insertions.

cancer biology↗

bioRxiv2024

Cell-autonomous GP130 activation suppresses prostate cancer development via STAT3/ARF/p53-driven senescence and confers an immune-active tumor microenvironment

Prostate cancer ranks as the second most frequently diagnosed cancer in men worldwide. Recent research highlights the crucial roles GP130-mediated signaling pathways play in the development and progression of various cancers, particularly through hyperactivated STAT3 signaling. Here, we find that genetic cell-autonomous activation of the GP130 receptor in prostate epithelial cells triggers active STAT3 signaling and significantly reduces tumor growth in vivo. Mechanistically, genetic activation of GP130 signaling mediates senescence via the STAT3/ARF/p53 axis and anti-tumor immunity via recruitment of cytotoxic T-cells, ultimately impeding tumor progression. In prostate cancer patients, high GP130 mRNA expression levels correlate with better recurrence-free survival, increased senescence signals and a transition from an immune-cold to an immune-hot tumor. Our findings reveal a context-dependent role of GP130/STAT3 in carcinogenesis and a tumor-suppressive function in prostate cancer development. We challenge the prevailing concept of blocking GP130/STAT3 signaling as functional prostate cancer treatment and instead propose cell-autonomous GP130 activation as a novel therapeutic strategy.

cancer biology↗

bioRxiv2023

JUN mediates senescence and immune cell recruitment to prevent prostate cancer progression

BackgroundProstate cancer develops through malignant transformation of the prostate epithelium in a stepwise, mutation-driven process. Although activator protein-1 transcription factors such as JUN have been implicated as potential oncogenic drivers, the molecular programs contributing to prostate cancer progression are not fully understood. MethodsWe analyzed JUN expression in clinical prostate cancer samples across different stages and investigated its functional role in a Pten-deficient mouse model. We performed histopathological examinations, transcriptomic analyses and explored the senescence-associated secretory phenotype in the tumor microenvironment. ResultsElevated JUN levels characterized early-stage prostate cancer and predicted improved survival in human and murine samples. Immune-phenotyping of Pten-deficient prostates revealed high accumulation of tumor-infiltrating leukocytes, particularly innate immune cells, neutrophils and macrophages as well as high levels of STAT3 activation and IL-1{beta} production. Jun depletion in a Pten-deficient background prevented immune cell attraction which was accompanied by significant reduction of active STAT3 and IL-1{beta} and accelerated prostate tumor growth. Comparative transcriptome profiling of prostate epithelial cells revealed a senescence-associated gene signature, upregulation of pro-inflammatory processes involved in immune cell attraction and of chemokines such as IL-1{beta}, CCL3 and CCL8 in Pten-deficient prostates. Strikingly, JUN depletion reversed both, senescence and senescence-associated immune cell infiltration and consequently accelerated tumor growth. ConclusionsOur results suggest that JUN acts as tumor-suppressor and decelerates the progression of prostate cancer by transcriptional regulation of senescence- and inflammation-associated genes. This study opens avenues for novel treatment strategies that could impede disease progression and improve patient outcomes.

cancer biology↗

bioRxiv2023

The Minimal Dataset for Cancer of the 1+Million Genomes Initiative

For a real impact on healthcare, precision cancer medicine requires accessibility and interoperability of clinical and genomic data across centres and countries. Due to the heterogeneous digitization in Europe and worldwide, the definition of models for standardised data collection and usability becomes mandatory if countries want to work together on this mission. The European Union 1+Million Genomes (1+MG) initiative, supported by the Horizon 2020 Beyond 1 Million Genomes project, aims at outlining data models, guidance, best practices, and technical infrastructures for transnational access to sequenced genomes, including cancer genomes. Within the framework of the cancer-focused Working Group 9, we developed the 1+MG-Minimal Dataset for Cancer (1+MG-MDC)-a data model encompassing 140 items and organized in eight conceptual domains for the collection of cancer-related clinical information and genomics metadata. The 1+MG-MDC, which results from a multidisciplinary effort, leverages pre-existing models and emphasizes the annotation and traceability of multiple aspects relevant to the complex longitudinal path of the cancer disease and its treatment. We strived to make the 1+MG-MDC easy to adopt, yet comprehensive, addressing the needs of both clinicians and researchers. We will periodically revise and update it to ensure it remains fit for purpose. We propose the 1+MG-MDC as a model to create homogeneous databases, which would, in turn, guide discussions on clinical and genomic features with prognostic or therapeutic value and foster real-world data research.

cancer biology↗

bioRxiv2023

Mobile retroelements induced by hypomethylating agents are restricted to transpose in myeloid malignancies

Retroelements (RE) present in the human genome are silenced via multiple mechanisms, including DNA methylation, to prevent their potentially mutagenic effect. RE activity, demonstrated by their expression and somatic retrotransposition events, is deregulated in multiple tumor types but not in leukemia. We hypothesized that treatment with hypomethylating agents (HMA), commonly used in myelodysplastic syndromes and acute myeloid leukemia, could lead to increased RE activity and somatic retrotranspositions, and contribute to disease progression. We induced expression of ORF1p protein encoded by long interspersed nuclear element-1 (L1) after 72h treatment with HMA in DAMI and HL-60 cell lines. ORF1p was predominantly localized in the cytoplasm, as evidenced by fluorescent microscopy of the DAMI cell line. To study whether long-term HMA therapy may induce somatic retrotranspositions, we (i) treated both cell lines for four weeks, (ii) analyzed a cohort of 17 MDS patients before and on treatment with HMA. Using a previously established sensitive NGS-based method, no RE events were identified. To conclude, we show that although HMA induces the expression of L1-encoded proteins in tumor myeloid cell lines, de novo somatic retrotransposition events do not arise during the long-term treatment of MDS patients and myeloid cell lines with these agents.

cancer biology↗

bioRxiv2020

Lyn controls chemotaxis and motility of CLL cells via phosphorylation of ROR1.

Chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) are malignancies characterized by the dependence on B-cell receptor (BCR) signaling and by the high expression of the cell surface receptor ROR1. Both, BCR and ROR1 are therapeutic targets in these diseases and the understanding of their mutual cross talk is thus of direct therapeutic relevance. In this study we analyzed the role of Lyn, a kinase from the Src family, as a mediator of the BCR-ROR1 crosstalk. We confirm the functional interaction between Lyn and ROR1 and demonstrate that Lyn kinase efficiently phosphorylates ROR1 in its kinase domain and aids the recruitment of an E3 ligase c-CBL. The absence of Lyn in Lyn KO Maver-1 cells produced by CRISPR-Cas9 resulted in the increased ROR1 cell surface levels and deregulated migratory properties. Similar correlations between ROR1 surface dynamics, levels of active Lyn and chemotactic properties were confirmed in primary CLL samples. Our data establish Lyn-mediated phosphorylation of ROR1 as a point of crosstalk between BCR and ROR1 signaling pathways.

cancer biology↗

bioRxiv2016

GLASS: assisted and standardized assessment of gene variations from Sanger sequence trace data

MotivationSanger sequencing remains the reference method for sequence variant detection, especially in a clinical setting. However, chromatogram interpretation often requires manual inspection and in some cases considerable expertise. Additionally, variant reporting and nomenclature is typically left to the user, which can lead to inconsistencies.\n\nResultsWe introduce GLASS, a tool built to assist with the assessment of gene variations in Sanger sequencing data. Critically, it provides a standardized variant output as recommended by the Human Genome Variation Society.\n\nAvailabilityThe program is freely available online at http://bat.infspire.org/genomepd/glass/.\n\nContactnikos.darzentas@gmail.com, malcikova.jitka@fnbrno.cz\n\nSupplementary informationSupplementary data are available at Bioinformatics online.

bioinformatics↗