Biology subjects

Louis, L.

Publications and source records attributed to Louis, L..

5 recordsLinked to original sources

bioRxiv2026

RBFOX2 restrains oncogenic cell plasticity in Group 3 medulloblastoma

Cancer cell plasticity underlies tumor progression, metastasis and therapeutic resistance, yet how RNA-binding proteins regulate malignant state transitions remains poorly defined. Here, we identify the splicing regulator RBFOX2 as a suppressor of oncogenic cell plasticity in Group 3 medulloblastoma (MB). OTX2 antagonizes RBFOX2 by directing an opposing alternative splicing program that mirrors developmental origins and controls cytoskeletal dynamics and cell state transitions. Mechanistically, OTX2 alters the RBFOX2 RNA-binding landscape, limiting RBFOX2 engagement at cytoskeletal loci and suppressing exon inclusion. RBFOX2 loss rewires splicing and transcriptional outputs to promote highly plastic proliferative, mesenchymal-like and undifferentiated cellular states associated with enhanced oncogenic properties. Consistent with these findings, RBFOX2low states mark highly plastic cell populations in patient tumors and xenografts, positioning RBFOX2 as a determinant of malignant cell stability. Together, these findings establish RBFOX2 as a developmental gatekeeper that restrains malignant cell plasticity through coordinated control of cytoskeletal gene programs.

cancer biology↗

bioRxiv2025

Long lasting non-cellular reactions in sterile soils recapitulates most of the intermediates of the Krebs cycle

Over the past decade, chemical evidence has emerged that non-enzymatic metabolic pathways, such as the Krebs cycle, may have existed before cellular life on the primitive Earth. However, the question of whether non-cellular reactions analogous to cell respiration metabolism are still "active" in todays biosphere and whether they contribute to CO2 emissions in contemporary ecosystems remains open. In the present study, we investigated the long-term fate (> 6 months) of organic substrates supplied in sterilised soils in which cell life was not detectable. Through a series of analytical studies performed on the water-extractable fraction of soil exometabolites using chromatography, mass spectrometry and isotope labelling, we demonstrate that sterile soil matrix incubated with [13C6]-glucose and [13C6]-citrate can spontaneously generate intermediates of the Krebs cycle, alongside by-products such as acetate and formate. These findings support the hypothesis that extracellular metabolisms (EXOMETs) form a network of non-cellular reactions resembling metabolic pathways involved in aerobic respiration and anaerobic fermentation of cells. This research not only provides insights into the chemical continuity between chemistry and biochemistry but also raises questions about the implications of non-cellular pathways for soil ecosystem functioning and carbon fluxes in the contemporary biosphere.

biochemistry↗

bioRxiv2025

Mutations in specific MT5-MMP domains prevent the accumulation of toxic APP metabolites and serve as templates for peptide-based therapeutics in cell models of Alzheimer's disease

Our prior work established a pivotal role for membrane-type 5-matrix metalloproteinase (MT5-MMP) in Alzheimers disease (AD) pathogenesis, particularly through its C-terminal transmembrane (TM) and intracellular (IC) domains, which influence the fate of major toxic metabolites of toxic amyloid precursor protein (APP) metabolites, particularly C99 and A{beta}. Hypothesizing that modifications in these domains could modulate C99 and A{beta} levels, we engineered MT5-MMP variants with deletions or substitutions in the TM/IC domains or specific IC amino acid clusters. When co-transfected into human cell lines accumulating C99, certain IC domain mutations promoted C99 degradation and reduced A{beta} levels, while other mutations had divergent effects. High content imaging further revealed that MT5-MMP IC domain modification altered C99 subcellular trafficking within the endomembrane system, impacting its processing. Proximity ligation assays confirmed the importance of the IC domain in MT5-MMP colocalization and potential interaction with C99. To translate these findings, we synthetized peptides mimicking the MT5-MMP IC domain, incorporating mutations that reduce C99 and/or A{beta} levels. One peptide effectively lowered C99 levels in an in vitro AD model. Overall, this study highlights the importance of specific amino acids in the C-terminal domains of MT5-MMP for regulating C99 and A{beta} metabolism. It also provides new insights for developing MT5-MMP-based therapeutic strategies against AD, exploiting the unique properties of specific mutations in MT5-MMP to prevent toxic accumulation of C99 and A{beta}. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=86 SRC="FIGDIR/small/655451v3_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@a6b04aorg.highwire.dtl.DTLVardef@1800721org.highwire.dtl.DTLVardef@542505org.highwire.dtl.DTLVardef@4a6d7b_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGRAPHICAL ABSTRACTC_FLOATNO C_FIG

cell biology↗

bioRxiv2024

A Bag-Of-Motif Model Captures Cell States at Distal Regulatory Sequences

Deciphering the intricate regulatory code governing cell-type-specific gene expression is a fundamental goal in genetics. Current methods struggle to capture the complex interplay between gene distal regulatory sequences and cell context. We developed a computational approach, BOM (Bag-of-Motifs), which represents cis-regulatory sequences by the type and number of TF binding motifs it contains, irrespective of motif order, orientation, and spacing. This simple yet powerful representation allows BOM to efficiently capture the complexity of cell-type-specific information encoded within these sequences. We apply BOM to mouse, human, and zebrafish distal regulatory regions, demonstrating remarkable accuracy. Notably, the method outperforms more complex deep learning models at the same task using fewer parameters. BOM can also uncover cross-species sequence similarities unrecognized by genome alignments. We experimentally validate our in silico predictions using enhancer reporter assay, showing that motifs with the most significant explanatory power are sequence determinants of cell-type specific enhancer activity. BOM offers a novel systematic framework for studying cell-type or condition-specific cis-regulatory sequences. Using BOM, we demonstrate the existence of a highly predictive sequence code at distal regulatory regions in mammals driven by TF binding motifs.

bioinformatics↗

bioRxiv2020

MT5-MMP controls APP metabolism and the fate of beta-CTF/C99 and Abeta through proteolytic-dependent and -independent mechanisms relevant for Alzheimer's disease

We previously discovered the implication of membrane-type 5-matrix metalloproteinase (MT5-MMP) in Alzheimers disease AD pathogenesis. Here we shed new light on pathogenic mechanisms by which MT5-MMP controls APP processing and the fate of amyloid beta peptide (A{beta}), its precursor C99 and C83. We found in HEK carrying the APP Swedish familial mutation (HEKswe) that MT5-MMP-mediated processing of APP that releases the soluble 95 kDa form (sAPP95), was hampered by the removal of the C-terminal non-catalytic domains of MT5-MMP. Catalytically inactive MT5-MMP variants increased the levels of A{beta} and promoted APP/C99 sorting in the endo-lysosomal system. We found interaction of C99 with the C-terminal portion of MT5-MMP, the deletion of which caused a strong degradation of C99 by the proteasome, preventing A{beta} accumulation. These findings reveal novel mechanisms for MT5-MMP control of APP metabolism and C99 fate involving proteolytic and non-proteolytic actions mainly mediated by the C-terminal part of the proteinase.

neuroscience↗