Biology subjects

Huot, M.-E.

Publications and source records attributed to Huot, M.-E..

3 recordsLinked to original sources

bioRxiv2026

RAPTOR-targeted Antisense Oligonucleotides Restrict Pathological mTORC1 Activity in GATOR1-dependent Disease

Loss-of-function mutations in the GATOR1 complex (NPRL2, NPRL3, and DEPDC5) are among the most common genetic causes of epilepsy. These mutations impair amino acid-dependent regulation of mTORC1 and cause hyperactive signaling, neuronal hyperexcitability, astrocytic metabolic remodeling, seizures, and early mortality. Here, we report the development of antisense oligonucleotides (ASOs) targeting RAPTOR, an mTORC1 scaffolding subunit, to correct pathological mTORC1 hyperactivity caused by defective upstream regulation. RAPTOR-targeted ASO treatment reduced RAPTOR expression in mouse and human systems and dampened mTORC1 signaling in GATOR1-deficient models. ASO-mediated RAPTOR reduction rescued neuronal hyperexcitability, corrected astrocytic mitochondrial dysfunction, and suppressed spontaneous seizures in vivo. A single treatment significantly extended longevity across neuronal and astrocytic models of GATOR1 deficiency. Collectively, these findings establish RAPTOR-targeted ASOs as a mechanism-based therapeutic approach that durably corrects cellular and circuit-level consequences of GATOR1 deficiency. By tuning RAPTOR abundance, this strategy provides a therapeutic framework for mTORC1-driven epilepsies and related diseases.

neuroscience↗

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

eIf2α-regulated translation modulates the early adhesion of mesenchymal-like cells

Cellular invasion is a complex process that requires several interdependent biological mechanisms, which are initiated by changes in adhesion that establish a morphology favorable for migration. Hence, the regulation of adhesion potential is a rate-limiting step in metastasis. Our previous work revealed that de novo translation is necessary to regulate the adhesion of mesenchymal-like cells; however, the underlying translational regulatory mechanism and the identity of newly synthesized proteins needed for the adhesion process remain unidentified. Here, we identify a mechanotransduction pathway linking force-mediated protein unfolding to translational reprogramming via the activation of the integrated stress response (ISR). Specifically, we demonstrate that phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2) during early adhesion events leads to selective translation of mRNAs encoding proteins critical for adhesion complex formation, mechanosensing, and contractility. These findings uncover a mechanosensitive translational control axis that links intracellular force generation to cell adhesion and stress adaptation, with implications for understanding mesenchymal cell adhesion and morphological behavior

cell biology↗