Biology subjects

Gurdziel, K.

Publications and source records attributed to Gurdziel, K..

5 recordsLinked to original sources

bioRxiv2026

Novel biologically relevant small RNA-sequencing alignment tool LevenMap for alignment to database of non-coding RNAs

A crucial aspect of the bioinformatics workflow in small RNA-sequencing is the alignment of reads to a database of reference ncRNAs. Alignment algorithms such as Bowtie, Burrows-Wheeler Aligner (BWA), and Spliced Transcripts Alignment to a Reference (STAR) - which are designed for aligning reads to a reference genome - are typically used. Aligning short RNA-sequenced reads to a database of non-coding RNAs (ncRNAs) is fundamentally a different task than aligning longer reads to a genome due to ncRNAs (i) having roughly the same number of nucleotides as the reads being aligned and (ii) being subsequences of other ncRNAs. To account for these differences, we developed the novel alignment algorithm LevenMap. Of all reads which exactly matched a reference ncRNA in a publicly available dataset, LevenMap aligned 100.0% of them to their respective ncRNA while all other aligners mapped less than 40% of these reads to their corresponding ncRNA. Furthermore, the mean ratio (length of read) / (length of corresponding reference ncRNA) of all aligned reads was 1.0 and 0.998 for LevenMap with at most zero and one mismatch(es) allowed, respectively; this ratio was no more than 0.51 for all other aligners. Overall, LevenMap is designed to account for the nuances of aligning small RNA-sequencing data to a database of reference ncRNAs and yields more biologically relevant counts compared to traditional aligners in this context. LevenMap is free and publicly available on GitHub: https://github.com/hdlugas/LevenMap.

bioinformatics↗

bioRxiv2025

Single-Cell Comparison of Schwann and Fibroblast Cells Reveals Distinct Transcriptional Programs in NF1-Associated Neurofibromas

Neurofibromatosis type 1 (NF1) is an inherited tumor predisposition syndrome characterized by the development of benign peripheral nerve sheath tumors, most commonly cutaneous neurofibromas (cNFs) and plexiform neurofibromas (pNFs). Although both tumor types arise from Schwann cells and share NF1 loss as a genetic driver, they differ markedly in growth behavior, microenvironmental context, and clinical outcomes, with pNFs carrying risk of malignant transformation. To define transcriptional programs that underlie these differences, we performed an integrative single-cell RNA sequencing analysis of Schwann cells and fibroblasts from cNF and pNF tumors, alongside NF1-expressing reference populations derived from human skin and nerve. This approach enabled us to disentangle NF1-dependent transcriptional changes from tissue-of-origin effects. We identified distinct Schwann cell states that separated tumor from non-tumor populations and further distinguished cNFs from pNFs, highlighting both shared disease-associated features and subtype-specific adaptations. These findings establish a framework for understanding how NF1 loss interacts with developmental origin and tissue context to shape divergent tumor phenotypes and may inform strategies for therapeutic targeting in NF1-associated neurofibromas.

cancer biology↗

bioRxiv2025

Canagliflozin reprograms the aging hippocampus in genetically diverse UM-HET3 mice and attenuates Alzheimer's-like pathology

Aging is the strongest risk factor for cognitive decline and Alzheimers disease (AD), yet the mechanisms underlying brain aging and their modulation by pharmacological interventions remain poorly defined. The hippocampus, essential for learning and memory, is particularly vulnerable to metabolic stress and inflammation. Canagliflozin (Cana), an FDA-approved sodium-glucose co-transporter 2 inhibitor (SGLT2i) for type 2 diabetes, extends lifespan in male but not female mice, but its impact on brain aging is unknown. Here, we used a multi-omics strategy integrating transcriptomics, proteomics, and metabolomics to investigate how chronic Cana treatment reprograms brain aging in genetically diverse UM-HET3 mice. In males, Cana induced mitochondrial function, insulin and cGMP-PKG signaling, and suppressed neuroinflammatory networks across all molecular layers, resulting in improved hippocampal-dependent learning and memory. In females, transcriptional activation of neuroprotective pathways did not translate to protein or metabolite-level changes and failed to rescue cognition. In the 5xFAD AD model, Cana reduced amyloid plaque burden, microgliosis, and memory deficits in males only, despite comparable peripheral glucose improvements in both sexes. Our study reveals sex-specific remodeling of hippocampal aging by a clinically available SGLT2i, with implications for AD pathology and lifespan extension, and highlights Canas potential to combat brain aging and AD through sex-specific mechanisms.

neuroscience↗

bioRxiv2025

Relationship between melanoma vemurafenib tolerance thresholds and metabolic pathway choice and Wnt signaling involvement

Vemurafenib constitutes an important therapeutic for BRAFV600 mutant melanomas, but despite high initial response rates, resistance to BRAF and MEK inhibitors quickly develops. Here, we performed an integrative analysis of metabolomic consequences and transcriptome alterations to uncover mechanisms involved in adaptive vemurafenib resistance (VemR) development and their relationship with vemurafenib tolerance thresholds. We developed BRAFV600E isogenic models of VemR utilizing M14 and A2058 lines, and patient-derived melanomas with V600E or normal BRAF to verify vemurafenib selectivity. MEK or PI3K inhibitors only partially inhibited VemR cell proliferation, indicating cross-resistance to these inhibitors. MITF and {beta}-catenin levels were induced and treatment with Wnt/{beta}-catenin inhibitor ICG-001 restored vemurafenib sensitivity with concomitant reductions in {beta}-catenin-regulated gene expressions, phospho-ERK1/2, and VemR-induced mitochondrial mass and respiration. Targeted metabolite, MitoPlate-S1, Mito-stress and transcriptome/metabolomic analysis showed that melanoma cells with elevated vemurafenib tolerance thresholds such as A2058 VemR cells utilize Wnt/{beta}-catenin signaling for mitochondrial metabolism while VemR cells with low tolerance such as M14 VemR cells rely on Wnt/{beta}-catenin signaling for pentose phosphate pathway. Pathways associated with cytokine-cytokine receptor, ECM receptor, and neuroactive ligand receptor interactions were similarly enriched in BRAFV600E patient-derived melanoma as M14 and A2058 cells whereas distinct pathways involving cell cycle, DNA replication, Fanconi anemia and DNA repair pathways are upregulated in wild type BRAF expressing patient derived melanoma. These data show for the first time that the metabolic pathway choices made by VemR BRAF mutant melanomas are controlled by vemurafenib tolerance and endurance thresholds and Wnt/{beta}-catenin signaling plays a central role in coordinating expression of genes controlling VemR and metabolic pathway shifts.

cancer biology↗

bioRxiv2024

Impact of genomic background and developmental state on signaling pathways and response to therapy in Glioblastoma patient-derived cells

Glioblastoma (GBM) tumors represents diverse genomic epigenomic, and transcriptional landscapes, with significant intratumoral heterogeneity that challenges standard of care treatments involving radiation (RT) and the DNA-alkylating agent temozolomide (TMZ). In this study, we employed targeted proteomics to assess the response of a genomically-diverse panel of GBM patient-derived cancer stem cells (CSCs) to astrocytic differentiation, growth factor withdrawal and traditional high fetal bovine serum culture. Our findings revealed a complex crosstalk and co-activation of key oncogenic signaling in CSCs and diverse patterns of response to these external stimuli. Using RNA sequencing and DNA methylation, we observed common adaptations in response to astrocytic differentiation of CSCs across genomically distinct models, including BMP-Smad pathway activation, reduced cholesterol biosynthesis, and upregulation of extracellular matrix components. Notably, we observed that these differentiated CSC progenies retained a subset of stemness genes and the activation of cell survival pathways. We also examined the impact of differentiation state and genomic background on GBM cell sensitivity and transcriptional response to TMZ and RT. Differentiation of CSCs increased resistance to TMZ but not to RT. While transcriptional responses to these treatments were predominantly regulated by p53 in wild-type p53 GBM cells, its transcriptional activity was modulated by the differentiation status and treatment modality. Both mutant and wild-type p53 models exhibited significant activation of a DNA-damage associated interferon response in CSCs and differentiated cells, suggesting this pathway may play a wider role in GBM response to TMZ and RT. Our integrative analysis of the impact of GBM cell developmental states, in the context of genomic and molecular diversity of patient-derived models, provides valuable insights for pre-clinical studies aimed at optimizing treatment strategies.

cancer biology↗