Biology subjects

Hebert, S.

Publications and source records attributed to Hebert, S..

7 recordsLinked to original sources

bioRxiv2026

AMPK-dependent FLCN phosphorylation activates a survival response to hypoxia

Adaptation to low oxygen tensions is required to survive physiological and pathological stress conditions. We discovered an adenosine monophosphate-activated protein kinase (AMPK)-dependent, hypoxia-specific survival pathway through transcription factors (TFEB, TFE3). This pathway is distinct from nutrient sensing and independent of GAP Activity Towards Rags 1 (GATOR1). Mechanistically, AMPK phosphorylates the tumor suppressor folliculin (FLCN) at a highly conserved serine, inhibiting its GAP activity towards the Rag-GTPases, resulting in mechanistic target of rapamycin complex 1 (mTORC1) inhibition, TFE3 activation, resulting in lysosomal and mitochondrial biogenesis essential for hypoxia adaptation. TFEB/3 activity correlates with the hypoxia signature in hypoxic tumor areas. Cancer patients with elevated TFEB/3 activity show poor survival, specifically in hypoxia. These findings identify the AMPK-FLCN-TFE3 axis as a therapeutic target in tumors.

biochemistry↗

bioRxiv2026

A multimodal single-cell atlas of the adolescent brain reveals gene regulatory networks linking development to disease risk

Adolescence represents a critical window of brain maturation when many neuropsychiatric disorders first emerge, yet the molecular mechanisms driving this developmental period remain incompletely understood. To address this gap, we generated a high-resolution multimodal cell atlas of the developing adolescent brain using paired single-nucleus RNA and ATAC sequencing (snRNA-seq + snATAC-seq) from cortex, hippocampus, and amygdala tissue of six donors aged 6-15 years, profiling 88,658 high-quality nuclei. Integrative analyses identified 36 enhancer-driven gene regulatory networks (eGRNs) with significant age-dependent dynamics in the transition from childhood to adolescence. The majority of adolescence-associated eGRNs were active in oligodendrocytes and their precursors, reflecting active oligodendrogenesis and myelin remodeling during this developmental period. Notably, age-associated cis-regulatory elements were enriched for expression quantitative trait loci (eQTLs) and colocalized with genetic variants linked to both neurodevelopmental and neurodegenerative disorders, suggesting that regulatory networks may be shared across normal adolescent brain development and disease vulnerability. This multimodal cell atlas provides a valuable resource for understanding the human adolescent brain and offers new insights into the molecular origins of neuropsychiatric disorders.

neuroscience↗

bioRxiv2024

A diverse landscape of FGFR alterations and co-mutations defines novel therapeutic strategies in pediatric low-grade gliomas

Alterations in Fibroblast growth factor receptor (FGFR)-family proteins frequently occur as oncogenes in many cancers, including a subset of pediatric gliomas. Here, we performed a genomic analysis of 11,635 gliomas across ages and found that 4.5% of all gliomas harbor FGFR alterations including structural variants (SV) and single nucleotide variants (SNV), with an incidence of almost 10% in pediatric gliomas. FGFR family members are differentially enriched by age, tumor grade, and histological subtype, with FGFR1-alterations associated with glioneuronal histologies and pediatric low-grade gliomas. Across development, we find FGFR1 expression in both neuronal and glial precursors, while FGFR3 expression is largely restricted to astrocytic lineages. Leveraging novel isogenic model systems, we confirm FGFR1 alterations to be sufficient to activate MAPK and mTOR signaling, drive gliomagenesis, activate neuronal transcriptional programs and exhibit sensitivity to MAPK pathway inhibitors, including pan-FGFR inhibitors. Models driven by FGFR1 SVs exhibited different patterns of sensitivity compared to those driven by SNVs. Finally, we performed a retrospective analysis of clinical responses in children diagnosed with FGFR-driven gliomas and found that targeted MAPK or FGFR-inhibition with currently available inhibitors is largely associated with stability of disease. This study provides key insights into the biology of FGFR1-altered gliomas, therapeutic strategies to target them and associated challenges that still need to be overcome.

cancer biology↗

bioRxiv2023

Targeting the dependence on PIK3C3-mTORC1 signaling in dormancy-prone breast cancer cells blunts metastasis initiation

Halting breast cancer metastatic relapses following primary tumor removal and the clinical dormant phase, remains challenging, due to a lack of specific vulnerabilities to target during dormancy. To address this, we conducted genome-wide CRISPR screens on two breast cancer cell lines with distinct dormancy properties: 4T1 (short-term dormancy) and 4T07 (prolonged dormancy). We discovered that loss of class-III PI3K, Pik3c3, revealed a unique vulnerability in 4T07 cells. Surprisingly, dormancy-prone 4T07 cells exhibited higher mTORC1 activity than 4T1 cells, due to lysosome-dependent signaling occurring at the cell periphery. Pharmacological inhibition of Pik3c3 counteracted this phenotype in 4T07 cells, and selectively reduced metastasis burden only in the 4T07 dormancy-prone model. This mechanism was also detected in human breast cancer cell lines in addition to a breast cancer patient-derived xenograft supporting that it may be relevant in humans. Our findings suggest dormant cancer cell-initiated metastasis may be prevented in patients carrying tumor cells that display PIK3C3-peripheral lysosomal signaling to mTORC1. Statement of SignificanceWe reveal that dormancy-prone breast cancer cells depend on the class III PI3K to mediate a constant peripheral lysosomal positioning and mTORC1 hyperactivity. Targeting this pathway might blunt breast cancer metastasis.

cancer biology↗

bioRxiv2021

Sauna-like conditions or menthol treatment reduce tau phosphorylation through mild hyperthermia

In Alzheimers disease (AD), hyper-phosphorylation and aggregation of tau correlates with clinical progression and represents a valid therapeutic target. A recent 20-year prospective study revealed an association between moderate to high frequency of Finnish sauna bathing and a lower incidence of dementia and AD, but the molecular mechanisms underlying these benefits remain uncertain. Here, we tested the hypothesis that sauna-like conditions could lower tau phosphorylation by increasing body temperature. We observed a decrease in tau phosphorylation in wild-type and hTau mice as well as in neuron-like cells when exposed to higher temperatures. These effects were correlated with specific changes in phosphatase and kinase activities, but not with inflammatory or heat-shock responses. We also used a drug strategy to promote thermogenesis. Topical application of menthol led to a sustained increase in body temperature in hTau mice concomitant with a significant decrease in tau phosphorylation. Our results suggest that sauna-like conditions or menthol treatment could lower tau pathology through mild hyperthermia, and may provide promising therapeutic strategies for AD and other tauopathies.

neuroscience↗

bioRxiv2020

Satellite cell expansion is mediated by P-eIF2α dependent Tacc3 translation

Translational control of gene expression is an important regulator of adult stem cell quiescence, activation and self-renewal. In skeletal muscle, quiescent satellite cells maintain low levels of protein synthesis, mediated in part through the phosphorylation of eIF2 (P-eIF2). Pharmacological inhibition of the eIF2 phosphatase with the small molecule sal003 maintains P-eIF2 and permits the expansion of satellite cells ex vivo. Paradoxically, P-eIF2 also increases the translation of specific mRNAs, which is mediated by P-eIF2 dependent readthrough of inhibitory upstream open reading frames (uORFs). Here, we ask whether P-eIF2 dependent mRNA translation enables expansion of satellite cells. Using transcriptomic and proteomic analyses, we show a number of genes associated with the assembly of the spindle pole to be upregulated at the level of protein, without corresponding change in mRNA levels, in satellite cells expanded in the presence of sal003. We show that uORFs in the 5UTR of mRNA for the mitotic spindle stability gene Tacc3 direct P-eIF2 dependent translation. Satellite cells deficient for TACC3 exhibit defects in expansion, self-renewal and regeneration of skeletal muscle. SignificanceTranslational control of gene expression has emerged as an important regulator of adult stem cell populations, which maintain low levels of protein synthesis. In adult muscle stem cells, or satellite cells, a portrait of translational control has emerged whereby multiple repression mechanisms prevent the translation of specific mRNAs. It remains unclear how other mRNAs escape repression and are efficiently translated. We show that within the context of low global rates of protein synthesis, satellite cell expansion occurs through the selective translation of Tacc3 mRNA. Tacc3 deficient satellite cells expand poorly, leading to defects in skeletal muscle regeneration. Our study provides a more complete picture of translational control of gene expression in adult stem cell populations.

cell biology↗

bioRxiv2019

Alzheimer’s genetic risk factor FERMT2 (Kindlin-2) is regulated by risk allele-binding of miR-4504 and leads to synaptic dysfunction in an APP-dependent manner

Although APP metabolism is being intensively investigated, a large fraction of its modulators are yet to be characterized. In this context, we combined two genome-wide high-content screenings to assess the functional impact of miRNAs and genes on APP metabolism and the signaling pathways involved. This approach highlighted the involvement of FERMT2 (or Kindlin-2), a genetic risk factor of Alzheimers disease (AD), as a potential key modulator of axon guidance; a neuronal process that depends on the regulation of APP metabolism. We found that FERMT2 directly interacts with APP to modulate its metabolism and that FERMT2 under-expression impacts axonal growth, synaptic connectivity and long-term potentiation in an APP-dependent manner. Lastly, the rs7143400-T allele, which is associated with an increased AD risk and localized within the 3UTR of FERMT2, induced a down-regulation of FERMT2 expression through binding of miR-4504 among others. This miRNA is mainly expressed in neurons and significantly overexpressed in AD brains compared to controls. Altogether, our data provide strong evidence for a detrimental effect of FERMT2 under-expression in neurons and insight on how this may influence AD pathogenesis.

pathology↗