Biology subjects

Tichy, B.

Publications and source records attributed to Tichy, B..

6 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↗

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↗

bioRxiv2022

Cell Tree Rings: the shape of somatic evolution as a human aging timer

Biological age is typically estimated using biomarkers whose states have been observed to correlate with chronological age. A persistent limitation of such aging clocks is that it is difficult to establish how the biomarker states are related to the mechanisms of aging. Somatic mutations could potentially form the basis for a more fundamental aging clock since the mutations are both markers and drivers of aging and have a natural timescale. Cell lineage trees inferred from these mutations reflect the somatic evolutionary process and thus, it has been conjectured, the aging status of the body. Such a timer has been impractical thus far, however, because detection of somatic variants in single cells presents a significant technological challenge. Here we show that somatic mutations detected using single-cell RNA sequencing (scRNA-seq) from thousands of cells can be used to construct a cell lineage tree whose structure correlates with chronological age. De novo single-nucleotide variants (SNVs) are detected in human peripheral blood mononuclear cells using a modified protocol. A default model based on penalized multiple regression of chronological age on 31 metrics characterizing the phylogenetic tree gives a Pearson correlation of 0.81 and a median absolute error of [~]4 years between predicted and chronological age. Testing of the model on a public scRNA-seq dataset yields a Pearson correlation of 0.85. In addition, cell tree age predictions are found to be better predictors of certain clinical biomarkers than age alone, for instance glucose, albumin levels and leukocyte count. The geometry of the cell lineage tree records the structure of somatic evolution in the individual and represents a new modality of aging timer. In addition to providing a numerical estimate of Cell Tree Age, it unveils a temporal history of the aging process, revealing how clonal structure evolves over life span. Cell Tree Rings complements existing aging clocks and may help reduce the current uncertainty in the assessment of geroprotective trials.

genomics↗

bioRxiv2022

Mimicking tumor cell heterogeneity of colorectal cancer in a patient-derived organoid-fibroblast model

Patient-derived organoid (PDO) cancer models are generated from epithelial tumor cells. Although they reflect the molecular tumor characteristics, they lack the complexity of the tumor microenvironment, which is a key driver of tumorigenesis and therapy response. Here, we present a colorectal cancer (CRC) organoid model that incorporates epithelial cells and stromal fibroblasts from the same patient. Molecular characterization of primary cancer associated fibroblasts (CAFs) and matched normal fibroblasts (NF) revealed proteomic, secretome and gene expression differences in pathways associated with tumor related fibroblast function. Further, CAFs retained higher motility compared to NFs in vitro. Importantly, both CAFs and NFs supported cancer cell proliferation in 3D co-cultures, without the addition of classical niche factors. PDOs grown together with fibroblasts displayed a larger cellular heterogeneity of tumor cells compared to mono-cultures, and closely resembled the in vivo tumor morphology. This was also confirmed by the calculation of cellular proportions of epithelial cell subtypes in organoid mono-versus co-cultures, which were inferred through bioinformatics deconvolution of bulk RNA sequencing data using published single cell RNA sequencing datasets from CRC tissues. Additionally, we observed a mutual crosstalk between tumor cells and fibroblasts in the co-cultures. This was manifested by majorly deregulated pathways such as cell-cell communication and extracellular matrix remodeling in the organoids. For the fibroblasts, we observed enhanced expression of tumor induced marker genes and cytokines characteristic for myo- and immunogenic fibroblasts. This model will be vital as a physiological personalized tumor model to study disease mechanisms and therapy response in CRC. One Sentence SummaryPatient matched fibroblasts support tumor organoid growth in 3D co-culture and maintain intratumoral cellular heterogeneity and histo-morphology.

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↗