Biology subjects

Leroux, E.

Publications and source records attributed to Leroux, E..

3 recordsLinked to original sources

bioRxiv2026

SPARC mediates tumour-stroma intercellular communication through endosomal regulation of Delta and Notch signalling

Tumour progression relies on reciprocal communication between genetically altered cancer cells and surrounding stromal cells. While the genetic alterations that initiate tumorigenesis have been extensively studied, the dysregulated feedback signalling provided by co-opted stromal cells remains poorly understood. Here, we used a Drosophila cancer model to address this question and identified the matricellular protein SPARC as a mediator of tumour-stroma communication. SPARC is produced by mesenchymal cells and transferred into epithelial tumour cells, where it is internalized through the endocytic pathway. Following uptake, SPARC accumulates in Rab7 positive late endosomes and colocalize with the Notch ligand Delta. SPARC internalization promotes endosomal enlargement and reduces endosome dynamics. Increased SPARC levels in epithelial tumours indirectly attenuate Notch signalling activity through at least altered Delta trafficking. We further identify the N-terminal acidic domain of SPARC as specifically required for its targeting to Delta-associated endosomes. Together, our findings uncover a stromal feedback mechanism by which SPARC modulates Notch signalling through endosomal regulation during tumour development.

developmental biology↗

bioRxiv2025

Astrocyte and mitochondrial footprints in brain-derived extracellular vesicles predict tau pathology

Tauopathies are neurodegenerative disorders characterized by abnormal tau aggregation, with primary 3R (e.g., Picks disease, PiD) and 4R (e.g., progressive supranuclear palsy, PSP) variants posing a significant diagnostic challenge. Here, we examined brain-derived extracellular vesicles (BD-EVs) isolated from the prefrontal cortex of PiD (3R), PSP (4R), and non-demented controls (CTRL) to determine if these vesicles reflect disease-specific proteomic signatures. We found that while tau pathology does not substantially alter BD-EV concentration or the enrichment of core vesicular markers, it does influence their size distribution and protein cargo. BD-EV samples from PiD patients exhibited a greater abundance of small vesicles and distinct protein profiles when compared to PSP and CTRL. Weighted Gene Co-expression Network Analysis (WGCNA) identified four key protein modules to account for variance between patient groups Endoplasmic Reticulum, Mitochondria, Microtubules, and Trivalent Inorganic Cation Transport. In PiD, astrocyte-derived mitochondrial proteins were significantly elevated, whereas neuronal microtubule-related proteins were diminished relative to both PSP and CTRL. Notably, changes in the mitochondrion and microtubule modules enhanced the detection of PiD pathology. Cellular origin annotation revealed a marked shift in BD-EV composition: PiD samples exhibited an increased astrocytic signature, while both PiD and PSP showed a reduction in neuronal proteins compared to CTRL. Crucially, the enrichment of astrocytic mitochondrial and endoplasmic reticulum proteins, alongside reduced neuronal proteins, correlated strongly with the severity of tau pathology (AT8-stained aggregates) in patient brains. These findings demonstrate that BD-EVs capture tau isoform-specific cellular and molecular alterations, offering a window into disease mechanisms at the neuron-glia interface. By linking distinct protein signatures and their cellular origins to tau pathology severity, our results highlight the potential of BD-EV profiling as a biomarker strategy for distinguishing between and monitoring the progression of 3R and 4R tauopathies.

neuroscience↗

bioRxiv2023

Accumulation of Tau in Extracellular Vesicles Disturbs the Astrocytic Mitochondrial System

Tauopathies are neurodegenerative disorders involving the accumulation of tau isoforms in cell subpopulations such as astrocytes. The origins of the 3R and 4R isoforms of tau that accumulate in astrocytes remain unclear. Extracellular vesicles (EVs) were isolated from primary neurons overexpressing 1N3R or 1N4R tau or from human brain extracts (progressive supranuclear palsy or Pick disease patients or controls) and characterized (electron microscopy, nanoparticle tracking analysis (NTA), proteomics). After the isolated EVs were added to primary astrocytes or human iPSC-derived astrocytes, tau transfer and mitochondrial system function were evaluated (ELISA, immunofluorescence, MitoTracker staining). We demonstrated that neurons in which 3R or 4R tau accumulated had the capacity to transfer tau to astrocytes and that EVs were essential for the propagation of both isoforms of tau. Treatment with tau-containing EVs disrupted the astrocytic mitochondrial system, altering mitochondrial morphology, dynamics and redox state. Although similar levels of 3R and 4R tau were transferred, 3R tau-containing EVs were significantly more damaging to astrocytes than 4R tau-containing EVs. Moreover, EVs isolated from the brain fluid of patients with different tauopathies affected mitochondrial function in astrocytes derived from human iPSCs. Our data highlight that tau pathology spreads to surrounding astrocytes via EVs-mediated transfer and modify their function.

neuroscience↗