Biology subjects

Beaumont, E.

Publications and source records attributed to Beaumont, E..

3 recordsLinked to original sources

bioRxiv2026

Rab8a-positive vesicles transport Wnt8a along cytonemes in zebrafish embryogenesis.

Wnt signalling is a conserved pathway that orchestrates key developmental processes by regulating cell fate, proliferation, and tissue organisation. While the production and secretion of Wnt ligands are well characterised, less is known about how lipid-modified Wnts are delivered for long-range communication. Recently, cytonemes - actin-based signalling filopodia - have been identified as transporters of Wnts over distances to target specific cells in embryogenesis. Here, we characterise Rab8a-dependent vesicular trafficking as a crucial step in this process. Using human cell lines and zebrafish embryos, we show that Wnt ligands, such as Wnt8a, are transported with their carrier protein Wntless (Wls) in Rab8a-positive vesicles along cytonemes, where they fuse at the tips to enable hand-over and signal activation in neighbouring cells. Disruption of Rab8a function results in the intracellular retention of Wnt8a, reduces Wnt spreading and paracrine signalling, and alters embryonic patterning, consistent with reduced Wnt/{beta}-catenin function. Conversely, Rab8a activation enhances Wnt8a dissemination, leading to increased long-range signalling and, consequently, patterning defects in embryogenesis. Our findings uncover a dedicated intracellular trafficking route for Wnt delivery to and along cytonemes, offering new insights into how the spatial precision of Wnt spreading in vertebrate tissues is achieved.

developmental biology↗

bioRxiv2025

Establishment of human glioblastoma cell culture collection

Glioblastoma (GBM) is a highly aggressive primary brain cancer with poor prognosis (<15 months), highlighting the urgent need for more effective therapies. As current treatments are not effective, the need for a deeper understanding of the biology of GBM cells, including how they reprogram their metabolism to support their aberrant and uncontrolled growth, is critical. To this end, we established a collection of 41 human glioma cell lines derived from freshly resected tumour tissues from 99 patients. We characterized 12 of these cell lines by combining histologic, genetic, stem cell derivation and self-renewal, and metabolomic analyses. Histological and genetic profiles included IDH mutation status, Ki-67 proliferation index, ATRX status, mutant TP53 expression, chromosome 10q loss, EGFR amplification, and MGMT promoter methylation. Of these, only p53 mutation expression status showed weak segregation of the cell lines into 2 separate metabolic groups based on amino acid levels, but none showed an effect on stem cell derivation or self-renewal. Further characterization of these 12 cell lines revealed significant metabolic and phenotypic differences when comparing mesenchymal versus proneural gene expression subtyping. We show significant increases in TCA cycle metabolites in mesenchymal-like GBM cells and higher overall metabolic activity compared to proneural-like cells. These findings highlight the complexity of GBM and the need for personalized treatments that consider the metabolome of each subtype as a potential therapeutic avenue.

cancer biology↗

bioRxiv2022

Validation of a small molecule inhibitor of PDE6D-RAS interaction with potent anti-leukemic effects

RAS mutations prevalent in high-risk leukemia have been linked to relapse and chemotherapy resistance. Efforts to directly target RAS proteins have been largely unsuccessful. However, since RAS-mediated transformation is dependent on signaling through the RAS-related C3 botulinum toxin substrate (RAC) small GTPase, we hypothesized that targeting RAC may be an effective therapeutic approach in RAS mutated tumors. Here we describe multiple small molecules capable of inhibiting RAC activation in acute lymphoblastic leukemia cell lines. One of these, DW0254, also demonstrates promising anti-leukemic activity in RAS-mutated cells. Using chemical proteomics and biophysical methods, we identified the hydrophobic pocket of phosphodiester 6 subunit delta (PDE6D), a known RAS chaperone, as a target for this compound. Inhibition of RAS localization to the plasma membrane upon DW0254 treatment is associated with RAC inhibition through a phosphatidylinositol-3-kinase/AKT-dependent mechanism. Our findings provide new insights on the importance of PDE6D-mediated transport for RAS-dependent RAC activation and leukemic cell survival.

cancer biology↗