Biology subjects

Daubon, T.

Publications and source records attributed to Daubon, T..

7 recordsLinked to original sources

bioRxiv2026

TileScope quantifies spatial gene expression relationships beyond colocalization

Gene expression patterns within the same tissue region can exhibit similar correlation or enrichment, but still differ in their organization within regions and at their boundaries. We present TileScope, a framework for analysing genes and transcriptional programs within predefined tissue regions, their components and their contacts with neighbouring regions. TileScope combines regional enrichment, within-region correlation, cross-correlation over distance and expression differences near specific boundaries. Repeated spatial partitions and consensus aggregation show how these measurements depend on the grouping of spots or cells. Across 30 controlled constructions derived from glioblastoma and hepatocellular carcinoma data representing ten spatial expression scenarios, combined measurements separated arrangements that individual statistics left ambiguous, including coincident patches, gradients and expression localised at region boundaries. In 30 human glioblastoma sections, TileScope distinguished shared regional enrichment from internal covariation and identified hypoxia-associated expression localised at region boundary despite negligible within-region correlation. In newly acquired Visium profiles of control and myeloid-targeted MCT1-knockout (KO) orthotopic GL261 mouse gliomas, proliferation and myeloid programs were enriched in tumour peripheries but showed opposite within-periphery-region correlations. Proliferation was higher near the tumour-facing boundary in both samples, whereas myeloid expression was higher near the tumour-facing boundary in the control and farther within periphery in the KO condition. Xenium applications on glioblastoma and breast cancer samples demonstrated feasibility with irregularly spaced individual cells and different regional annotations. TileScope provides spatially explicit descriptions of gene and program relationships, linking their organization within tissue compartments to their sensitivity to aggregation.

bioinformatics↗

bioRxiv2026

SpacePath enables pathway and molecular-family analysis beyond annotation ambiguity in spatial metabolomics and lipidomics

Mass spectrometry imaging (MSI) maps metabolites and lipids in tissue with spatial resolution, but molecular identity remains partly resolved: single ions match multiple candidate compounds, and most detected metabolites and lipids fall outside canonical biochemical pathways. We developed SpacePath, a computational framework that retains ion-to-compound ambiguity, scores canonical pathways across tissue locations, and groups assignments that were unmapped to pathways into de novo molecular families by chemical similarity. Pathway mappings covered on average only 1% of molecular assignments, whereas the combined SpacePath representation covered 24% of pooled assignments. Benchmarking on four public spatial lipidomics datasets (healthy mouse brain, cerebellum, a demyelination model, and human bladder cancer) recovered previously reported spatial patterns. In newly acquired glioblastoma xenograft datasets, SpacePath identified lipid programs specific to tumor and surrounding brain, and SpiderMass-MS/MS independently confirmed four tumor-associated features from a de novo family, refining the initial MS1 assignments. SpacePath extends the spatial interpretation of MSI data beyond canonical pathways while preserving annotation uncertainty.

bioinformatics↗

bioRxiv2026

Microbiota-gut-brain axis modulation drives glioblastoma progression and therapy resistance

Glioblastoma is a highly aggressive brain tumour with poor prognosis, whose aetiology, progression, and therapeutic resistance remain incompletely understood. While the microbiota-gut-brain axis has emerged as a key regulator of neurological disorders, its role in glioblastoma biology and treatment response is still largely unexplored. Using a clinically relevant immunocompetent murine model combining glioblastoma stem cell implantation, dextran sodium sulfate-induced gut inflammation, and a full Stupp-like therapeutic protocol, we investigated bidirectional gut-brain communication in glioblastoma. Tumour growth and recurrence were monitored by bioluminescence imaging, tumour transcriptomic profiles were analysed by RNA sequencing, and brain and colon tissues were subjected to histological and molecular analyses. Gut microbiota composition was assessed by 16S rRNA sequencing, while systemic metabolites and cytokines were quantified in plasma. Cross-compartment association bioinformatic analyses were performed to correlate multi-organ readouts. Gut inflammation enhanced glioblastoma growth and promoted tumour recurrence following therapy. Tumour progression was associated with increased infiltration of immunosuppressive macrophages, whereas recurrence correlated with elevated oxidative DNA damage. Remarkably, glioblastoma exerted systemic immunomodulatory effects, attenuating intestinal and systemic inflammatory responses, and induced profound remodelling of gut microbiota composition and predicted metabolic function, including enrichment of Akkermansia and depletion of Lactobacillus. Systemic metabolic profiling was investigated as a route of communication within the gut-brain axis and revealed adaptations in DSS-treated mice associated with tumour burden and therapeutic response. Multi-compartment correlation and multivariable association analyses identified specific bacterial genera and circulating metabolites associated with tumour volume, intestinal inflammation, and genomic instability. These findings uncover a dynamic, bidirectional microbiota-gut-brain axis in glioblastoma and identify intestinal inflammation as a critical determinant of tumour progression and therapeutic outcome. Targeting gut disturbances and microbiota-associated metabolic pathways may represent novel strategies to modulate glioblastoma aggressiveness and treatment response.

cancer biology↗

bioRxiv2024

Exploiting a metabolic vulnerability in brain tumour stem cells using a brain-penetrant drug with safe profile

Glioblastoma (GB) remains one of the most treatment refractory and fatal tumour in humans. GB contains a population of self-renewing stem cells, the brain tumour stem cells (BTSC) that are highly resistant to therapy and are at the origin of tumour relapse. Here, we report, for the first time, that mubritinib potently impairs stemness and growth of patient-derived BTSCs harboring different oncogenic mutations. Mechanistically, by employing bioenergetic assays and rescue experiments, we provide compelling evidence that mubritinib acts on complex I of the electron transport chain to impair BTSC stemness pathways, self-renewal and proliferation. Global gene expression profiling revealed that mubritinib alters the proliferative, neural-progenitor-like, and the cell-cycling state signatures. We employed in vivo pharmacokinetic assays to establish that mubritinib crosses the blood-brain barrier. Using preclinical models of patient-derived and syngeneic murine orthotopic xenografts, we demonstrated that mubritinib delays GB tumourigenesis, and expands lifespan of animals. Interestingly, its combination with radiotherapy offers survival advantage to animals. Strikingly, thorough toxicological and behavioral studies in mice revealed that mubritinib does not induce any damage to normal cells and has a well-tolerated and safe profile. Our work warrants further exploration of this drug in in-human clinical trials for better management of GB tumours.

cancer biology↗

bioRxiv2022

Human glioblastoma cell motility depends on the activity of the cysteine metabolism enzyme 3-Mercaptopyruvate sulfurtransferase

Cancer cells in similar functional states are found in all glioblastoma, despite the genomic heterogeneity observed between and within these brain tumors. Metabolism being downstream of all signaling pathways regulating cell behaviors, we looked for metabolic weaknesses in link with motility, a key functional state for glioblastoma aggressiveness. A signature-driven data reduction approach highlighted motile cells present in thirty tumors from four independent single-cell transcriptomic datasets. Analyses integrating trajectory modeling disclosed, as characteristic of motile cells, enhanced oxidative stress coupled with mobilization of the cysteine metabolism enzyme 3-Mercaptopyruvate sulfurtransferase (MPST). The soundness of this prediction was verified using migration and invasion assays with patient-derived cells and tissue organoids. Pharmacological and genetic manipulations showed that enhanced ROS production and MPST activity are required for the cells motility. Biochemical assays indicated that MPST acts by protecting protein cysteine residues from dismal hyperoxidation. In vivo, MPST knockdown translated in reduced tumor burden, and a robust increase in mice survival. These results show that enhanced oxidative stress coupled with MPST mobilization plays a key role in glioblastoma cell motility.

cancer biology↗

bioRxiv2021

SLIT2-ROBO signaling in tumor-associated microglia/macrophages drives glioblastoma immunosuppression and vascular dysmorphia

SLIT2 is a secreted polypeptide that guides migration of cells expressing ROBO1&2 receptors. Herein, we investigated SLIT2/ROBO signaling effects in gliomas. In patients with glioblastoma (GBM), SLIT2 expression increased with malignant progression and correlated with poor survival and immunosuppression. Knockdown of SLIT2 in mouse glioma cells and patient derived GBM xenografts reduced tumor growth and synergized with immunotherapy to prolong survival. Tumor cell SLIT2 knockdown inhibited macrophage invasion and promoted a cytotoxic gene expression profile, which improved tumor vessel function and enhanced efficacy of chemotherapy and immunotherapy. Mechanistically, SLIT2 promoted microglia/macrophage chemotaxis and tumor-supportive polarization via ROBO1&2-mediated PI3K{gamma} activation. Macrophage Robo1&2 deletion and systemic SLIT2 trap delivery mimicked SLIT2 knockdown effects on tumor growth and the tumor microenvironment (TME), revealing SLIT2 signaling through macrophage ROBOs as a novel regulator of the GBM microenvironment and a potential immunotherapeutic target for brain tumors.

cancer biology↗

bioRxiv2021

TGF-beta promotes microtube formation in glioblastoma through Thrombospondin 1

Microtubes (MTs), cytoplasmic extensions of glioma cells, are important cell communication structures promoting invasion and treatment resistance through network formation. MTs are abundant in chemoresistant gliomas, in particular glioblastomas (GBMs), while they are uncommon in chemosensitive IDH-mutant and 1p/19q co-deleted oligodendrogliomas. To identify potential signaling pathways involved in MT formation we performed a bioinformatics analysis of TCGA data showing that the TGF-{beta} pathway is highly activated in GBMs compared to oligodendroglial tumors. In particular we observed that signaling pathways involved in extracellular matrix organization are differentially expressed between these tumor entities. Using patient-derived GBM stem cell lines, we demonstrated that TGF-{beta}1 stimulation promotes enhanced MT formation and communication via Calcium signaling. Inhibition of the TGF-{beta} pathway significantly reduced MT formation and its associated invasion in vitro and in vivo. Downstream of TGF-{beta}, we identified thrombospondin 1 (TSP1) as a potential mediator of MT formation in GBM through SMAD activation. TSP1 was upregulated upon TGF-{beta} stimulation and enhanced MT formation, which was inhibited by TSP1 shRNAs in vitro and in vivo. In conclusion, TGF-{beta} and its downstream mediator TSP1 are important mediators of the MT network in GBM and blocking this pathway could potentially help to break the complex MT driven invasion/ resistance network.

cancer biology↗