Biology subjects

Kurowska, A.

Publications and source records attributed to Kurowska, A..

6 recordsLinked to original sources

bioRxiv2026

EPHA4 Regulates the Transition between Mesenchymal and Hybrid States in TNBC

Metastatic progression in triple-negative breast cancer (TNBC) is strongly influenced by epithelial-mesenchymal plasticity (EMP), which enables transitions between epithelial, hybrid epithelial/mesenchymal (E/M), and mesenchymal cell states. While mesenchymal cells are highly invasive and resistant to therapy, hybrid E/M states confer advantages during metastatic colonization. Both mesenchymal and hybrid states therefore contribute to tumor aggressiveness through distinct mechanisms. However, the molecular regulation governing transitions between mesenchymal and hybrid E/M states remains poorly understood. Here, we identify EPHA4 as a regulator of this transition in TNBC. EPHA4 expression is enriched in mesenchymal TNBC cells, and genetic knockout of EPHA4 in MDA-MB-231 xenograft and 4T1 syngeneic models induces a shift toward hybrid E/M phenotypes. This transition reduces cellular invasion while enhancing metastatic colonization, consistent with the clinical observations of decreased EPHA4 expression in secondary metastases compared to primary tumors. Despite compensatory changes in other Eph/ephrin family members following EPHA4 loss, EPHA4 deficiency is sufficient to drive this phenotypic shift. These findings identify EPHA4 as a regulator of cancer cell plasticity in TNBC and highlight the therapeutic complexity of targeting pathways that govern metastatic state transitions.

cancer biology↗

bioRxiv2026

Mapping Disease Transitions from Premalignant, Asymptomatic to Advanced Myeloma through Integrative Epigenomic and Transcriptional Analyses

AbstractMultiple myeloma (MM) evolves from asymptomatic precursor conditions through progressive genetic and epigenetic remodeling, yet the regulatory mechanisms driving the development toward more active stages of the disease remain poorly understood. Here, we integrated bulk-based paired chromatin accessibility and activation, and transcriptomic profiling across disease stages to map regulatory remodeling during myeloma development. We identified a progressive increase in chromatin accessibility; furthermore, this epigenetic reconfiguration is accompanied by a stage-dependent shift from promoter-centered regulation in precursor states toward enhancer-dominated transcriptional control in active MM. Motif enrichment and regulatory network analyses identified both established and previously underappreciated transcription factors (TFs), including members of the IRF, MEF2, and FOX families, associated with disease-stage-specific transcriptional programs. Among these, MEF2D and FOXK2 emerged as candidate regulators of pathways involved in cell survival and chemotaxis. Functional perturbation demonstrated that MEF2D depletion markedly impaired MM cell viability, whereas inhibition of either MEF2D or FOXK2 reduced chemotactic migration. Together, these findings provide a stage-resolved framework of epigenetic and transcriptional remodeling across myeloma development, revealing regulatory programs established in precursor conditions and progressively reinforced during disease evolution, while identifying candidate transcriptional dependencies with potential biological and therapeutic relevance.

cancer biology↗

bioRxiv2024

Spatial Transcriptomics Reveals a Myeloma Cell Architecture with Dysfunctional T-Cell Distribution, Neutrophil Traps, and Inflammatory Signaling

The bone marrow (BM) is a complex tissue where spatial relationships influence cell behavior, signaling, and function. Consequently, understanding the whole dynamics of cellular interactions requires complementary spatial techniques that preserve and map the architecture of cell populations in situ. We successfully conducted spatial transcriptional profiling using Visium Spatial Gene Expression in formalin-fixed paraffin-embedded (FFPE) BM samples obtained from healthy and Multiple Myeloma (MM) mouse models and patients, addressing the technical challenges of applying spatial technology to long bone samples. A custom data-analysis framework that combines spatial with single-cell transcriptomic profiles identified both the BM cellular composition and the existing cell relations. This allowed us to visualize the spatial distribution of transcriptionally heterogeneous MM plasma cells (MM-PC). We spatially delineated transcriptional programs associated with MM, including NETosis and IL-17-driven inflammatory signaling, which were inversely correlated to malignant PC-enriched regions. Furthermore, a gradient of MM-PC density spatially correlated with a shift from effector-to-exhausted T cell phenotypes. The translational relevance of our findings was confirmed using FFPE BM biopsies from MM patients with varying levels of malignant PC infiltration. In summary, we provide the first spatial transcriptomics analysis applied to a mouse and human mineralized bone tissue and illustrate the BM cellular architecture of MM, revealing deregulated mechanisms underlying MM intercellular communication.

cancer biology↗

bioRxiv2023

Uncovering the cis-regulatory program of early human B-cell commitment and its implications in the pathogenesis of B-cell acute lymphoblastic leukemia

Dysregulation of the early stages of B-cell lymphopoiesis, orchestrating the development of cellular immunity, may induce malignant transformations. Therefore, it is essential to characterize the gene regulatory network (GRN) driving B-cell lymphopoiesis in healthy individuals to uncover malignancy mechanisms. To this end, we generated a dataset that included paired human data for chromatin accessibility and gene expression in eight B-cell precursor stages, providing the first deep characterization of early B-cell lymphopoiesis, including the identification of regulatory elements and the reconstruction of the GRN. Using this data, we recapitulated well-known regulatory elements and revealed new regulons, such as ELK3, enriched in pro-B cells with a putative role in cell cycle progression. Moreover, a single-cell multi-omics analysis validated and enhanced the resolution of the regulatory landscape recovered by bulk data, revealing MYBL2 and ZNF367 as specific regulons of cycling cell states, and CEBPA associated with lymphoid multipotent progenitors (LMPPs). Importantly, this dataset enabled us to uncover B-cell acute lymphoblastic leukemia (B-ALL) triggers. We identified different cellular origins of malignant transformation depending on the B-ALL subtype, including the association of the ETV6-RUNX1 with pro-B cells and the increased expression of ELK3 in this ALL subtype. Overall, our dataset provides the most comprehensive atlas to date of early human B-cell regulation (B-rex; https://translationalbio.shinyapps.io/brex/), facilitating further understanding of B-cell differentiation in health and disease.

immunology↗

bioRxiv2023

Alternative splicing of the stress-sensitive regulator CIRBP sharpens the cellular response to bacterial infection

Cell autonomous responses to intracellular bacteria largely depend on gene expression reorganization. To gain isoform-level resolution into these regulations, we combined long- and short-read transcriptomic analyses of the response of intestinal epithelial cells to infection by the foodborne pathogen Listeria monocytogenes. Among the most striking isoform-based regulations, expression of the cellular stress response regulator CIRBP (cold-inducible RNA-binding protein) and of several SRSFs (serine/arginine-rich splicing factors) switched from canonical transcripts to nonsense-mediated decay-sensitive isoforms by inclusion of "poison exons". We showed that damage to host cell membranes caused by bacterial pore-forming toxins (listeriolysin O, perfringolysin, streptolysin, or aerolysin) led to the dephosphorylation of SRSF proteins via the inhibition of the kinase activity of CLK1, thereby driving CIRBP alternative splicing. CIRBP isoform usage was found to have consequences on infection, since selective repression of canonical CIRBP reduced intracellular bacterial load while that of the poison exon-containing isoform exacerbated it. Consistently, CIRBP-bound mRNAs were shifted towards stress-relevant transcripts in infected cells, with increased mRNA levels or reduced translation efficiency for some targets. Our results thus generalize the alternative splicing of CIRBP and SRSFs as a common response to biotic or abiotic stresses by extending its relevance to the context of bacterial infection.

molecular biology↗

bioRxiv2021

riboviz 2: A flexible and robust ribosome profiling data analysis and visualization workflow

MotivationRibosome profiling, or Ribo-seq, is the state of the art method for quantifying protein synthesis in living cells. Computational analysis of Ribo-seq data remains challenging due to the complexity of the procedure, as well as variations introduced for specific organisms or specialized analyses. Many bioinformatic pipelines have been developed, but these pipelines have key limitations in terms of functionality or usability. ResultsWe present riboviz 2, an updated riboviz package, for the comprehensive transcript-centric analysis and visualization of Ribo-seq data. riboviz 2 includes an analysis workflow built on the Nextflow workflow management system, combining freely available software with custom code. The package is extensively documented and provides example configuration files for organisms spanning the domains of life. riboviz 2 is distinguished by clear separation of concerns between annotation and analysis: prior to a run, the user chooses a transcriptome in FASTA format, paired with annotation for the CDS locations in GFF3 format. The user is empowered to choose the relevant transcriptome for their biological question, or to run alternative analyses that address distinct questions. riboviz 2 has been extensively tested on various library preparation strategies, including multiplexed samples. riboviz 2 is flexible and uses open, documented file formats, allowing users to integrate new analyses with the pipeline. Availabilityriboviz 2 is freely available at github.com/riboviz/riboviz. Supplementary information

bioinformatics↗