Biology subjects

Barthel, F.

Publications and source records attributed to Barthel, F..

5 recordsLinked to original sources

bioRxiv2026

Patient-Derived Glioma Models Preserve Tumor Heterogeneity and Identify Stearoyl-CoA Desaturase1 (SCD1) as a Candidate Biomarker for Precision Immunotherapy

Background: Pediatric and adult brain tumors, including glioblastoma, astrocytoma, ependymoma, and medulloblastoma, remain associated with poor prognosis despite advances in surgery, radiation, and chemotherapy. Therapeutic resistance, tumor heterogeneity, and treatment-related toxicity highlight the need for clinically relevant models that enable precision medicine and immunotherapy development. Methods: Freshly dispersed tumors (FDTs), low-passage patient-derived brain tumor (PBT) spheroid lines, and matched patient-derived xenograft (PDX) models were established from patients with primary brain tumors. Models were characterized using single-cell and bulk RNA sequencing, whole-exome sequencing, multiparameter flow cytometry, and immunohistochemistry. PBTs were compared with matched FDTs to evaluate model fidelity. Results: PBT lines were established in approximately 68% of cases and retained key patient-specific genomic alterations, including IDH1, MGMT, TP53, and PTEN, with expression of therapeutically relevant targets, including IL13R2, EGFR, HER2, WNT1, JAK1/2, and NOTCH1-4. Gene expression profiles of PBTs closely correlated with matched FDTs (R = 0.38, P = 0.0038). PBT and PDX models preserved intratumoral heterogeneity and non-clonal populations, enabling identification of therapy-resistant subclones during in vitro selection. Molecular analyses identified Stearoyl-CoA Desaturase1 (SCD1) as an overexpressed biomarker across glioma PBTs and matched patient tumors. Ingenuity Pathway Analysis identified SCD1 as an upstream regulator of EGFR-, TP53-, and CYCS-associated signaling networks implicated in tumor progression and immune suppression. Conclusions: Clinically relevant PBT and matched PDX models recapitulate molecular, transcriptional, and histopathological characteristics of primary brain tumors. These platforms provide tools for biomarker discovery, therapeutic testing, and precision immunotherapy development, while identifying SCD1 as a biomarker and therapeutic target in glioma.

cancer biology↗

bioRxiv2026

Chromosome-arm-specific telomere length governs dual modes of structural genome evolution in IDH-mutant astrocytoma

IDH-mutant astrocytomas maintain telomeres through the alternative lengthening of telomeres (ALT) pathway, producing extreme inter-arm telomere length heterogeneity, yet how this heterogeneity shapes structural genome evolution remains unknown. Using Oxford Nanopore long-read sequencing of 20 IDH-mutant astrocytomas, we profiled structural variants (SVs), copy number variants, extrachromosomal DNA (ecDNA) and measured allele-specific telomere lengths from individual long reads. We identified pervasive complex rearrangements, including chromothripsis and foldback events consistent with breakage-fusion-bridge cycles, and widespread ecDNAs. SV breakpoints were enriched at telomeric and centromeric regions regardless of local telomere length, revealing constitutive structural fragility. Arm-level telomere length analysis uncovered a dual-mode model: arms with short telomeres preferentially harbored breakage-associated events, while arms with long ALT-maintained telomeres were enriched for ecDNA and amplification-associated events. These findings identify chromosome-arm-specific telomere length as a determinant of structural genome evolution in ALT-driven tumors.

cancer biology↗

bioRxiv2025

Cell-Free DNA Reveals the Longitudinal Effects of Temozolomide Treatment and Host Co-Culture in Glioblastoma Models

Glioblastoma (GBM) is a highly aggressive brain tumor with limited options for longitudinal monitoring. We evaluated the potential of cell-free DNA (cfDNA) as a real-time biomarker of tumor burden under tightly controlled conditions. We measured the cfDNA release dynamics, fragmentation sizes, and variant allele frequencies (VAF) in patient-derived GBM cell cultures. Time series of cfDNA were collected and analyzed in treatment-naive monocultures, during temozolomide (TMZ) treatment, and in co-culture with normal human astrocyte (NHA) cells. Longitudinal collection of media from individual cultures demonstrated that cfDNA yield increased, indicating the ability to use cfDNA to track tumor burden over time. Using a co-culture system, we deconvoluted cfDNA admixtures by analyzing yield, fragment size patterns, and cell line-specific variants. The exclusive detection of NHA- and GBM-specific mutations confirmed the distinct contributions of each cell type. Finally, TMZ treatment of GBM cells prompted an increase in cfDNA yield and VAF, suggesting that the effects of therapy could be measured using cfDNA. These findings support cfDNA as a non-invasive biomarker for real-time monitoring of GBM progression and treatment response, with clinical potential as a liquid biopsy tool in glioblastoma management. KEY POINTSO_LIcfDNA yield and variant allele frequencies (VAFs) correlate with GBM tumor burden. C_LIO_LIcfDNA properties can be used to differentiate between cell types in a mixed population. C_LIO_LITMZ treatment increases cfDNA yield and VAFs, reflecting treatment response. C_LI IMPORTANCE OF THE STUDYThis study highlights the potential of cell-free DNA (cfDNA) as a non-invasive biomarker for monitoring glioblastoma (GBM) progression and treatment response. By utilizing in-vitro models, we demonstrate that cfDNA yield, fragmentation patterns, and variant allele frequencies (VAFs) can effectively identify treatment-induced changes, such as those induced by temozolomide (TMZ) treatment, providing insights into therapeutic response. These results have significant translational implications, as cfDNA could serve as a real-time liquid biopsy tool for monitoring GBM progression, assessing treatment efficacy, and identifying early signs of treatment resistance in clinical settings. The ability to track tumor dynamics non-invasively holds great promise for improving GBM patient management and guiding personalized therapeutic approaches.

cancer biology↗

bioRxiv2020

Single-cell multimodal glioma analyses reveal epigenetic regulators of cellular plasticity and environmental stress response

Glioma intratumoral heterogeneity enables adaptation to challenging microenvironments and contributes to universal therapeutic resistance. Here, we integrated 914 single-cell DNA methylomes, 55,284 single-cell transcriptomes, and bulk multi-omic profiles across 11 adult IDH-mutant or IDH-wild-type gliomas to delineate sources of intratumoral heterogeneity. We found that local DNA methylation instability, or epimutation burden, was elevated in more aggressive tumors, reflected intratumoral variability, linked with transcriptional disruption, and associated with environmental stress response. We show that the activation of cell-state specific transcription factors is impacted by epimutations and that loosened epigenetic control may facilitate cellular plasticity. Our analyses support that somatic copy number alterations (SCNAs) promote epigenetic instability and that SCNAs largely precede epigenetic and transcriptomic diversification during glioma evolution. We confirmed the link between genetic and epigenetic instability by analyzing larger cohorts of bulk longitudinally collected and spatially separated DNA methylation data. Increased DNA methylation instability was associated with accelerated disease progression, and recurrently selected DNA methylation changes were enriched for environmental stress response pathways. Our work provides an integrative framework to better understand glioma evolution and highlights the importance of epigenetic heterogeneity in shaping therapeutic response.

cancer biology↗

bioRxiv2017

Reconstructing the Molecular Life History of Gliomas

At the time of clinical presentation, the very heterogeneous group of pediatric and adult gliomas carry a wide range of diverse somatic genomic alterations. These include chromosome-sized gains and losses, focal amplification and deletions, rearrangements resulting in transcript fusions, small insertions/deletions, and point mutations. Tumor cells pay a penalty for maintaining these abnormalities which therefore must provide cells with a competitive advantage to become engrained into the glioma genome. Here, we propose a model for gliomagenesis consisting of five consecutive phases that glioma cells have traversed prior to diagnosis. Tumor growth is repressed by activated DNA damage response pathways and dysfunctional telomeres in physiological conditions. Disruption of the p16-RB-p53 pathway and the acquisition of a telomere maintenance mechanism can bypass these bottlenecks. We relate somatic alterations to each of these steps, in order to reconstruct the life history of glioma. Understanding the story that each glioma tells at presentation may facilitate the design of novel, more effective therapeutic approaches.\n\nKey ConceptsGlioma initiating event: The first event that initiates the clonal expansion of cells\n\nOncogene-induced senescence: Durable growth arrest triggered by continued oncogene exposure\n\nReplicative senescence: Durable growth arrest triggered via telomere dysfunction and activated DNA damage pathways\n\nCrisis: Widespread cell death triggered via telomere dysfunction\n\nSenescence bypass event: Any molecular alteration that bypasses or suppresses oncogene-induced senescence\n\nSenescence-associated secretory phenotype (SASP): Senescent cells secrete various immunogenic cytokines, growth factors and proteases into the microenvironment\n\nFunctional redundancy: Used to describe two or more genomic changes that provide overlapping functional effect\n\nNeutral evolution: changes due to stochastic allelic variation that do not affect fitness\n\nSelective sweep: The elimination of genetic variation following strong positive selection effectively reducing the tumor to a single clone\n\nClonal event: Somatic mutation or copy number event that is conserved across all tumor cells\n\nSubclonal event: Somatic mutation or copy number event that is only present in a subset (subclone) of tumor cells\n\nChromothripsis: A punctuated shattering of genomic DNA\n\nKataegis: Clustered regions of hypermutation\n\nPolyploidization: The multiplication of chromosome content in a cell\n\nBreakage fusion bridge (BFB) cycle: Cyclic fusion of uncapped telomeres, bridge formation during anaphase and subsequent breakage leading to unequal inheritance of DNA\n\nDicentric chromosome: Two fused chromosomes span across the mitotic spindle in anaphase, called dicentric because it has two centromeres\n\nDouble minute (DM) chromosome: Extra-chromosomal circular DNA segment lacking centromere(s) and telomeres\n\nImmortalization event: The last straw in the immortalization process that directly leads to telomere stabilization

cancer biology↗