Biology subjects

Umaru, B.

Publications and source records attributed to Umaru, B..

4 recordsLinked to original sources

bioRxiv2026

Integrated Multi-Omics Identifies Lineage-Dependent Myeloid Cells Recruitment and the APP-CD74 Axis as an Immunoregulatory Target in Pediatric High-Grade Glioma

Diffuse intrinsic pontine glioma (DIPG) is a devastating pediatric brain tumor with limited treatment options. Emerging evidence indicates infiltration of tumor-associated macrophages (TAMs) within tumor sites, accompanied by an immunosuppressive tumor microenvironment (TME). However, the mechanisms underlying macrophage recruitment and communication between TAMs and other cellular compartments within brain tumors remain poorly understood. Bulk RNA sequencing of 26 DIPG autopsy specimens with matched normal brain tissue, single-cell RNA sequencing data from eight DIPG patients integrated with public pediatric high-grade glioma (pHGG) datasets, and in vitro transwell and flow cytometry assays collectively indicated that DIPG tumors actively recruit monocytes through chemokine-mediated mechanisms. The chemokine expression of tumor cells is driven by a mesenchymal-like (MES-like) lineage state rather than histone mutations, as evidenced by significant correlation between MES-like lineage scores and chemokine expression scores across 46 pHGG cell lines. CellChat analysis identified APP-CD74 signaling as a prominent tumor cell-TAM interaction pathway, supported by immunofluorescence validation. Notably, APP expression was significantly reduced in DIPG tumor tissues compared with normal brain tissue at both the RNA and protein levels. Recombinant APP stimulation of THP-1-derived macrophages induced a robust proinflammatory response, including upregulation of M1-like markers, enrichment of interferon-related pathways, and elevated secretion of inflammatory cytokines. Collectively, these findings indicate that APP suppression in tumors attenuates the antitumor activity of TAMs and promotes an immunosuppressive microenvironment. Furthermore, protein modeling and docking analyses identified the APP-CD74 binding interface, providing a structural basis for therapeutic targeting.

immunology↗

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

BMI-1 Modulation and Trafficking During M Phase in Diffuse Intrinsic Pontine Glioma

BMI-1 (B cell-specific Moloney murine leukemia virus integration site 1) has been implicated in both normal and cancer cell biology. While the canonical function of BMI-1 involves epigenetic repression, novel extra-nuclear functions have been recently reported. In the present study, we demonstrate that the phosphorylation of BMI-1 in diffuse intrinsic pontine glioma (DIPG) cells occurs in M phase and that triggers simultaneous translocation of the phosphorylated BMI-1 to the cytoplasm. This translocation is mediated by the RanGTP-dependent transporter CRM1, also known as exportin. Furthermore, we uncovered a previously unidentified nuclear export signal (NES) in BMI-1 protein, suggesting an active transport type of modified BMI-1 mediated by CRM1. These findings associate BMI-1 phosphorylation with its trafficking in M phase. Collectively, this study sheds light on the molecular mechanisms underlying BMI-1 functions in DIPG, thereby potentially paving the way for the development of targeted therapeutic strategies related to M phase progression.

cancer biology↗

bioRxiv2025

Efficacy of DNA Methyltransferase Inhibitor Immune Priming Therapy in Combination with PD-1 Inhibitors to Treat High-Risk Pediatric Brain Tumors

BackgroundDespite intensive therapies, outcomes for high-risk pediatric brain tumors (PBTs) remain dismal, prompting the search for novel treatments. DNA methyltransferase inhibitors (DNMTi) have been shown to prime tumors to improve response to checkpoint inhibition. The aim of this study was to investigate the potential of decitabine (DAC), in combination with a PD-1 inhibitor, to improve survival in pediatric high-risk brain tumor models. MethodsAnalysis of human PBT datasets was performed to determine gene expression levels of immune cell associated markers. Tumor response to DAC, with or without a PD-1 inhibitor, was tested in murine models representing H3-wildtype diffuse intrinsic pontine glioma (DIPG), H3K27-mutant diffuse midline glioma (DMG), atypical teratoid rhabdoid tumor (ATRT), and medulloblastoma (MB). CyTOF analysis of allograft tumors was performed to characterize changes within the tumor microenvironment. ResultsAnalysis of PBT subtypes revealed heterogeneous expression of immune cell markers, checkpoint receptors, and MHC molecules. DAC treatment decreased DNA methylation and increased neoantigen expression in human and mouse tumor cells. DAC alone or in combination with a PD-1 inhibitor resulted in prolonged survival in syngeneic mouse models of DIPG and ATRT but not DMG and MB models. CyTOF analysis of mouse tumors revealed changes in local immune cell infiltration upon combination treatment. ConclusionsDAC in combination with a PD-1 inhibitor can alter the immune microenvironment in mouse tumor models. Changes were observed in H3-wildtype DIPG and ATRT models, suggesting that certain tumor subtypes may respond to checkpoint blockade after immune augmentation with DNMTi. Key PointsO_LIPBTs show heterogenous expression of immune cell infiltrates C_LIO_LIDAC or DAC plus a PD-1 inhibitor shows extension of survival in H3-wildtype DIPG and ATRT mouse models C_LIO_LIMyeloid-derived suppressor cell abundance could be a major contributing factor to treatment response C_LI Importance of the StudyChildren with high-risk PBTs face dismal outcomes. Immune checkpoint inhibitor (ICI) successes have been demonstrated in a variety of adult malignancies; however, such beneficial outcomes have not been realized in PBTs. Here we investigate single and combination treatment of DNMTi and PD-1 checkpoint inhibition in syngeneic mouse models of high-risk PBTs. Our results suggest that some H3-wildtype DIPG and ATRT tumor types may be responsive to checkpoint therapy post immunomodulation and warrant further investigation.

immunology↗