Biology subjects

Tabori, U.

Publications and source records attributed to Tabori, U..

7 recordsLinked to original sources

bioRxiv2026

Single-cell multi-omic analyses resolve the cellular diversity of ALK/ROS1/MET/NTRK-fused gliomas in infants and older children

Pediatric cancers are thought to arise from dysregulation of developmental programs, otherwise tightly regulated in time and space. Infant-type hemispheric gliomas (IHGs) arise in early childhood, driven by characteristic ALK/ROS1/MET/NTRK receptor tyrosine kinase (RTK) gene fusions. We dissected the cellular hierarchies of 24 fusion-positive gliomas, spanning infants through adolescents, using single-cell and single-nucleus RNA/ATAC-seq, and spatial transcriptomics. We identified five cancer cell states, with radial glia-like cells at the apex of a neoplastic hierarchy resembling neuronal- and glial-like trajectories. Neuronal-like cells were enriched in most IHGs but diminished in ROS1-fused IHGs and older patients. Integration of chromatin profiling revealed FOS/JUN-driven oncogenic programs and high inferred plasticity across all cancer cell populations. Myeloid cells, the most abundant non-neoplastic population, comprised distinct subgroups, suggesting context-dependent functions. Despite lacking high-order structure, spatial transcriptomics revealed discrete cellular niches within IHGs. Collectively, our findings elucidate the cellular states and developmental programs underlying IHGs and RTK-fused gliomas in older patients, opening new avenues for research and therapy innovation.

cancer biology↗

bioRxiv2026

hTERT Expression, Regulation, and Prognostic Significance in Pediatric Medulloblastoma

BackgroundTelomerase reactivation, a hallmark of many cancers, is associated with expression of its catalytic subunit, hTERT. However, the prognostic significance of telomere maintenance mechanisms in pediatric medulloblastoma remains poorly defined. MethodsIn this multi-institutional retrospective study of telomerase expression and hTERT regulation in newly diagnosed children with medulloblastoma, hTERT and MYC expression were assessed by qRT-PCR, normalized to non-neoplastic brain control samples. hTERT promoter methylation was analyzed using quantitative pyrosequencing and Illumina 450k methylation array. Cox proportional-hazard regression analyses evaluated the association of hTERT expression with progression-free survival (PFS) or overall survival (OS). Spearman correlation and Kruskal-Wallis tests correlated hTERT promoter methylation and expression and assessed variations among medulloblastoma subgroups, respectively. ResultsAmong 74 patients with available hTERT expression and outcome data, higher expression was associated with worse OS (HR=1.22, 95% CI: 1.01-1.47, p=0.036) and PFS (HR=1.17, 95% CI: 1.00-1.37, p=0.051) after adjusting for subgroup. Similar results were obtained when adjusting for metastatic status. Group 3 patients had the highest hTERT expression (p=0.001). Pyrosequencing data were available for 61 patients and 450k methylation array data for 292 patients. hTERT promoter was differentially methylated across subgroups with WNT followed by group 3 demonstrating the highest methylation on 450k (p<0.0001), findings that were confirmed by pyrosequencing. hTERT promoter methylation positively correlated with hTERT expression (Spearman correlation=0.42, p=0.02 by 450k and 0.34, p=0.007 by pyrosequencing). No significant correlation was observed between hTERT and MYC expression. ConclusionElevated hTERT expression is associated with worse PFS and OS in medulloblastoma across subgroups, supporting telomerase inhibition as a potential therapeutic strategy.

cancer biology↗

bioRxiv2025

Functionally distinct ALK and ROS1 fusions detected in infant-type hemispheric gliomas converge on STAT3 and SHP2 activation

ALK and ROS1 fusions are emerging as key drivers of infant-type hemispheric gliomas (IHG). With diverse gene partners, the impact of ALK and ROS1 oncoprotein heterogeneity on glioma biology remains unknown. We developed an integrative phospho-proteomic and transcriptomic approach to discover biological functions regulated by five IHG-associated fusions: CCDC88A::ALK, PPP1CB::ALK, GOPC::ROS1, CLIP1::ROS1 and KIF21A::ROS1. Here, we report fusion-specific oncogenic functions conferred by the 5 gene partner, including increased cell motility driven by microtubule-interacting fusions CCDC88A::ALK and CLIP1::ROS1. All studied fusions converged on a non-canonical STAT3 activation. Using affinity purification mass spectrometry, we identify SHP2 in direct interaction with all three ROS1 oncoproteins, but with none of the ALK oncoproteins, which in turn interact with SHC1/SHC3. ROS1 fusions phosphorylated SHP2 to a larger extent than ALK fusions, and analyses of downstream pathways suggested MAPK-independent, non-canonical SHP2-driven functions. Our findings reveal both common and fusion-specific dependencies, offering opportunities to optimize therapeutic strategies for pediatric gliomas.

cancer biology↗

bioRxiv2024

Targeting synthetic lethality between non-homologous end joining and radiation in very high-risk SHH medulloblastoma

Specific and biologically informed treatments for medulloblastoma, especially the highly lethal TP53 mutant SHH subgroup, remain elusive, where radiotherapy is the primary treatment option. Applying genome-wide CRISPR-Cas9 screening in combination with lethal doses of radiotherapy, we identified the main driver of radiation resistance in SHH medulloblastoma is loss of p53. A negative selection CRISPR-Cas9 screen across multiple models of Trp53-deficient SHH medulloblastoma revealed a strong synthetic lethal interaction between components of the non-homologous end-joining pathway and radiation, particularly DNA protein kinase (DNA-PK) and its binding partners. Both genetic and pharmacological perturbation of DNA-PK enhanced radiosensitivity in TP53-deficient SHH medulloblastoma, leading to cell death. In vivo treatment of somatic and germline TP53-mutant SHH medulloblastoma models with peposertib, a small-molecule inhibitor of DNA-PK, significantly improved survival when combined with radiotherapy, strongly supporting further clinical investigation.

cancer biology↗

bioRxiv2023

Single-strand mismatch and damage patterns revealed by single-molecule DNA sequencing

Mutations accumulate in the genome of every cell of the body throughout life, causing cancer and other genetic diseases1-4. Almost all of these mosaic mutations begin as nucleotide mismatches or damage in only one of the two strands of the DNA prior to becoming double-strand mutations if unrepaired or misrepaired5. However, current DNA sequencing technologies cannot resolve these initial single-strand events. Here, we developed a single-molecule, long-read sequencing method that achieves single-molecule fidelity for single-base substitutions when present in either one or both strands of the DNA. It also detects single-strand cytosine deamination events, a common type of DNA damage. We profiled 110 samples from diverse tissues, including from individuals with cancer-predisposition syndromes, and define the first single-strand mismatch and damage signatures. We find correspondences between these single-strand signatures and known double-strand mutational signatures, which resolves the identity of the initiating lesions. Tumors deficient in both mismatch repair and replicative polymerase proofreading show distinct single-strand mismatch patterns compared to samples deficient in only polymerase proofreading. In the mitochondrial genome, our findings support a mutagenic mechanism occurring primarily during replication. Since the double-strand DNA mutations interrogated by prior studies are only the endpoint of the mutation process, our approach to detect the initiating single-strand events at single-molecule resolution will enable new studies of how mutations arise in a variety of contexts, especially in cancer and aging.

genomics↗

bioRxiv2021

Life without mismatch repair

Mismatch repair (MMR) is a critical defence against mutation, but we lack quantification of its activity on different DNA lesions during human life. We performed whole-genome sequencing of normal and neoplastic tissues from individuals with constitutional MMR deficiency to establish the roles of MMR components, tissue type and disease state in somatic mutation rates. Mutational signatures varied extensively across genotypes, some coupled to leading-strand replication, some to lagging-strand replication and some independent of replication, implying that the various MMR components engage different forms of DNA damage. Loss of MSH2 or MSH6 (MutS), but not MLH1 or PMS2 (MutL), caused 5-methylcytosine-dependent hypermutation, indicating that MutS is the pivotal complex for repairing spontaneous deamination of methylated cytosines in humans. Neoplastic change altered the distribution of mutational signatures, particularly accelerating replication-coupled indel signatures. Each component of MMR repairs 1-10 lesions/day per normal human cell, and many thousands of additional events during neoplastic transformation. HighlightsO_LIMMR repairs 1-10 lesions/day in every normal cell and thousands more in tumor cells C_LIO_LIMMR patterns and rates are shaped by genotype, tissue type and malignant transformation C_LIO_LIMSH2 and MSH6 are pivotal for repairing spontaneous deamination of methylated cytosine C_LIO_LIReplication indels and substitutions vary by leading versus lagging strand and genotype C_LI

genomics↗

bioRxiv2018

Chromatin Blueprint Of Glioblastoma Stem Cells Reveals Common Drug Candidates For Distinct Subtypes

Chromatin accessibility discriminates stem from mature cell populations, enabling the identification of primitive stem-like cells in primary tumors, such as Glioblastoma (GBM) where self-renewing cells driving cancer progression and recurrence are prime targets for therapeutic intervention. We show, using single-cell chromatin accessibility, that primary GBMs harbor a heterogeneous self-renewing population whose diversity is captured in patient-derived glioblastoma stem cells (GSCs). In depth characterization of chromatin accessibility in GSCs identifies three GSC states: Reactive, Constructive, and Invasive, each governed by uniquely essential transcription factors and present within GBMs in varying proportions. Orthotopic xenografts reveal that GSC states associate with survival, and identify an invasive GSC signature predictive of low patient survival. Our chromatin-driven characterization of GSC states improves prognostic precision and identifies dependencies to guide combination therapies.

cancer biology↗