Biology subjects

Bure, C.

Publications and source records attributed to Bure, C..

2 recordsLinked to original sources

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↗

bioRxiv2025

Structural basis for NONO specific modification by the α-chloroacetamide compound (R)-SKBG-1

Among the many proteins involved in cancer progression an increasing number of RNA Binding Proteins (RBPs) are central to the function of a cell and tightly associated to genetic diseases as well as cancer appearance and progression. In a recent study, small molecule inhibitors have been identified as targeting NONO, a RBP known to be involved in mRNA splicing, DNA repair and membraneless organelles stability. Here we report the molecular basis of NONO-targeting by the -chloroacetamide (R)-SKBG-1. We explore the specific binding and enantiomer specificity of NONO towards (R)-SKBG-1 using mass spectrometry and structure determination. We have determined the crystal structure of (R)-SKBG-1-bound to NONO homodimer. This study sheds light on the conformational plasticity of (R)-SKBG-1 when covalently bound to NONO. Altogether these results give an experimental rationale for ligand modification and optimization in a future use as a drug against cancer. SIGNIFICANCEDBHS proteins form a family of three proteins encoded by three different and essential genes. They form obligate homodimers and heterodimers to fulfil their function. In the cell, they are involved in mRNA splicing, DNA repair and membraneless organelles formation. Recently, NONO has been identified as a target of small-molecule inhibitors in prostate cancer cells. Treatment with -chloroacetamide modifies a specific cysteine residue only found in NONO and not in its paralogue proteins SFPQ and PSPC1. Here we provide the molecular basis of -chloroacetamide covalent binding to NONO and we explore the enantiomer specificity of binding. We also demonstrate that -chloroacetamide can target NONO in homodimers and heterodimers and that both binding sites are equivalently modified. Finally, we provide show that -chloroacetamide binding to NONO is driven by the combination of covalent binding and conformational flexibility of the ligand. Altogether, we believe that this study provides useful information for ligand improvement aiming at targeting NONO in cancer cells. OUTLINEO_LINONO residue C145 is targeted by (R)-SKBG-1 C_LIO_LIThe two binding sites are equally modified in NONO homodimers C_LIO_LINONO is specifically targeted and not SFPQ and PSPC1 C_LIO_LI(R)-SKBG-1 adopts multiple conformations in the absence of RNA C_LI

biochemistry↗