Biology subjects

Gudenas, B.

Publications and source records attributed to Gudenas, B..

3 recordsLinked to original sources

bioRxiv2025

Human stem cell models for group 3 medulloblastoma uncover JARID1B as a regulator of the chromatin landscape.

Medulloblastoma (MB) is one of the most prevalent malignant brain tumors in children, with tremendous cognitive and neuroendocrine disability among survivors. Group 3 MB (G3MB) has poor overall survival at <50%, high frequencies of metastases, and no targeted therapies. Amplification of MYC and activation of TGF{beta} signaling occur frequently in G3MB. Many tumors have no reported mutations, suggesting epigenetic drivers. We here describe novel humanized models for G3MB from human induced pluripotent stem cells (hiPSC). By transducing hiPSC-derived neuroepithelial stem cells (NESC), we determined that: 1) both MYC and TGF{beta} effectors drove tumors in vivo; 2) MYC/TGF{beta}R1 in combination led to more aggressive tumors and resistance to clinical inhibitors of TGF{beta}, and 3) NESC-derived tumors clustered with human G3MB. To decipher mechanisms, we integrated RNA-sequencing with CUT&RUN (for MYC genomic localization and post-translational modification of histones). MYC-bound neural developmental genes were repressed in MYC/TGF{beta}R1 co-driven lines. Gene signatures associated with the Polycomb Repressive Complex (PRC) demarcated with H3K27me3; the histone mark directly regulated by PRC. We identified JARID1B, a MYC binding partner and H3K4me3 demethylase, as a regulator of repressed neural genes. Primary G3MB also showed increased levels of H3K27me3 concurrent with higher expression of JARID1B. Knockdown of JARID1B in human G3MB cell lines reduced growth, supporting potential as a therapeutic target. We conclude that a MYC-TGF{beta}-JARID1B axis represses target genes to drive G3MB and present new humanized models for G3MB to understand epigenetic dysregulation in G3MB.

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↗

bioRxiv2020

Patient-Derived Orthotopic Xenografts and Cell Lines from Pediatric High-Grade Glioma Recapitulate the Heterogeneity of Histopathology, Molecular Signatures, and Drug Response

Pediatric high-grade glioma (pHGG) is a major contributor to cancer-related death in children. In vitro and in vivo disease models reflecting the intimate connection between developmental context and pathogenesis of pHGG are essential to advance understanding and identify therapeutic vulnerabilities. We established 21 patient-derived pHGG orthotopic xenograft (PDOX) models and eight matched cell lines from diverse groups of pHGG. These models recapitulated histopathology, DNA methylation signatures, mutations and gene expression patterns of the patient tumors from which they were derived, and included rare subgroups not well-represented by existing models. We deployed 16 new and existing cell lines for high-throughput screening (HTS). In vitro HTS results predicted variable in vivo response to inhibitors of PI3K/mTOR and MEK signaling pathways. These unique new models and an online interactive data portal to enable exploration of associated detailed molecular characterization and HTS chemical sensitivity data provide a rich resource for pediatric brain tumor research.

cancer biology↗