Biology subjects

Durand, S.

Publications and source records attributed to Durand, S..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

Spermidine alleviates depression via control of the stress response

Depression is a stress-associated disorder, and it represents a major global health issue. Its pathophysiology is complex and remains insufficiently understood, with current medications often showing limited efficacy and undesirable side effects. Here, we identify imbalanced polyamine levels and dysregulated autophagy as key components of the acute stress response in humans, and as hallmarks of chronic stress and depressive disorders. Moreover, conventional antidepressant pharmacotherapy increases endogenous plasma concentrations of the polyamine spermidine exclusively in patients who respond to the treatment, suggesting a link between spermidine and successful outcomes. In a clinical trial, involving drug-naive depressed individuals, three weeks of spermidine supplementation increased autophagy and alleviated symptoms of depression. Behavioral and mechanistic findings of spermidine supplementation were validated in various mouse stress and depression models. In summary, spermidine supplementation mitigates polyamine dysregulation and stimulates autophagy under pathological stress conditions, offering a novel and well-tolerated treatment approach for stress-related depressive disorders.

neuroscience↗

bioRxiv2024

Maximizing meiotic crossover rate reveals the map of Crossover Potential

Meiotic crossovers are limited in number and unevenly distributed along chromosomes, both features often differing between sexes. The mechanisms imposing a different crossover landscape in female and male meiosis remain elusive. Here, we simultaneously disrupted multiple anti-crossover mechanisms in Arabidopsis and analyzed the whole genome sequence of thousands of female- and male-derived progenies. The largest crossover increase was reached in zyp1 recq4, with 12-fold in females and a 4.5-fold increase in males. Despite this unprecedented level of crossovers, fertility is marginally affected, opening new possibilities for plant breeding. Manipulating additional crossover regulators in zyp1 recq4 did not further elevate the frequency of crossovers, but modified the relative contributions of the two known crossover pathways. This suggests an upper limit was reached and the two pathways compete for a large but limited set of recombination intermediates. Remarkably, while wild-type crossover distribution differs markedly between sexes, the crossover landscapes of diverse mutants in both females and males converge to a single novel profile, which we termed Crossover Potential (COP). The COP profile, which we defined using 49,482 crossovers, can be accurately predicted using only sequence divergence and chromatin features. We propose that the COP represents the density of eligible recombination precursors, which is determined by genomic features and is thus identical in females and males. It suggests that the sexual dimorphism in the crossover landscape results exclusively from differential regulation of the likeness of precursors to mature into crossovers.

genetics↗

bioRxiv2024

Towards a standardised method for the characterisation and isolation of colorectal cancer stem cells by SdFFF and UHF-DEP: highlighted by transcriptomic analysis

Cancer stem cells (CSCs) play a crucial role in tumor heterogeneity and the progression of colorectal cancer (CRC). However, identifying and isolating CSCs remains challenging, as conventional methods, such as fluorescent or magnetic labeling, are time-consuming and require substantial technical and biological resources, limiting their clinical applicability. In this study, we evaluated the potential application of a previously established approach with glioma cells, combining sedimentation field-flow fractionation (SdFFF) with a label-free Ultra-High Frequency dielectrophoresis (UHF-DEP) biosensor, for isolating and identifying CRC CSC. The integration of the UHF-DEP biosensor with SdFFF enables the identification of CSCs without specific labeling, simplifying their analysis. To optimize this coupling, we standardized the mobile phase between the two technologies. Producing two CSC sub-populations eluted in Fraction 1 and Fraction 3. For the first time, transcriptomic analysis was employed to deepen our understanding of the genetic composition of the cells, complementing functional and phenotypic characterizations. From these characteristics, it emerged that F1 cells corresponded to precursors, while F3 cells could be considered CSC. The UHF-DEP biosensor demonstrated its ability to detect these differences, linking F3 to cells cultivated in defined medium (DM), used as a reference standard. Finally, transcriptomic analysis (RNA-seq) has deepened our understanding of the genetic profiles of these subpopulations, enriching the interpretation of their characteristics as CSCs. This in-depth approach will also contribute to a better understanding of the results obtained by the UHF-DEP biosensor.

cancer biology↗

bioRxiv2024

New proteomic signature in circulating extracellular vesicles from tumor-draining vein of lung adenocarcinomas patients

Identification of noninvasive prognostic biomarkers, allowing monitoring of frequently developed relapse in patients with locally advanced non-small cell lung cancer (NSCLC), still of primary importance. Tumor-draining vein (TDV) plasma samples, are known to be enriched in circulating cancer biomarkers compared to samples from peripheral vein (PV). Thus, we thought to investigate the proteomic profile of extracellular vesicles (EVs) from TDV compared to those from PV plasma samples of patients operated for NSCLC. Purified EVs from TDV and PV plasma samples were characterized for their size distribution and concentration using nanoparticles tracking analysis (NTA). Proteomic profiling of TDV-derived EVs and PV-derived EVs were further done using mass spectrometry (nanoLC-MS/MS) analysis. In parallel, proteomic profile of tumoral and non-tumoral adjacent counterpart tissues from patients with NSCLC were investigated. Twenty patients with NSCLC, treated by surgery with curative intent, were enrolled in this study. We showed that EVs from TDV plasma samples were significantly smaller than those from PV plasma samples. Interestingly, the concentration of TDV-derived EVs were significantly higher than PV-derived EVs. However, EVs concentration and size were not associated with tumor size or other clinical characteristics. Proteomic profiling showed that 9 of the 10 most overexpressed proteins in EVs from TDV samples compared to those from PV, were associated with lung cancer diagnosis and prognosis. Remarkably, 1 protein (SRPRB) was commonly upregulated in lung tumor tissues (as compared to non-tumoral counterparts) and in TDV-derived EVs (as compared to PV-derived EVs). In contrast, 12 proteins were found to be upregulated in TDV-derived EVs and downregulated in tumor tissues. In conclusion, all of these identified proteins, carried by EVs from TDV plasma samples, might represent promising novel biomarkers for NSCLC prognosis and predicting recurrences at early stages.

cancer biology↗

bioRxiv2024

Stimulus history, not expectation, drives sensory prediction errors in mammalian cortex

Hierarchical predictive coding (HPC) models have recently flourished in neuroscience1-9. Feedforward and feedback processing are at the heart of HPC models. Previous experimental studies using fMRI, EEG/MEG, and LFP9-11 do not reliably resolve feedback modulation from local computations and feedforward outputs. Here, using open-science8, multi-species, multi-area, high-density12, laminar neurophysiology13, we empirically test whether hierarchical predictive coding is a key component shaping cortical processing of visual stimuli. To isolate visual information processing and eliminate motor/reward confounders9-11, we use a no-report task. Our task leveraged so-called global oddballs (GO) as unpredictable, deviant stimuli that circumvent low-level adaptation. We examined their responses relative to local oddballs (LO) that we habituated into highly predictable priors. Four surprising findings in this dataset challenge many existing hierarchical predictive coding models. First, GO responses were exclusive to higher-order, more cognitive areas rather than early-to-mid visual cortex. Second, inhibitory interneuron-targeted optogenetics in primates and mice and waveform shape analysis in primates revealed no evidence that predictive suppression was implemented via these interneurons. Third, highly predictable LO responses dominated in over 50% of all neurons, including in higher-order cortex, which should have anticipated them, indicating limited evidence for predictive suppression. Lastly, prediction error responses evoked by GOs did not evoke feedforward processing. These results reveal circuit dynamics that govern how prediction shapes visual processing, motivating more neurally constrained predictive processing models.

neuroscience↗

bioRxiv2024

MutLgamma enforces meiotic crossovers in Arabidopsis thaliana

During meiosis, each chromosome pair experiences at least one crossover (CO), which directs their balanced segregation in addition to shuffling genetic information. COs tend to be away from each other, a phenomenon known as CO interference. The main biochemical pathway for CO formation, which is conserved in distant eukaryotes, involves the ZMM proteins together with the MLH1-MLH3 complex (MutL{gamma}). Here, we aim to clarify the role of MutL{gamma} in CO formation in Arabidopsis thaliana. We show that AtMutL{gamma} is partially dispensable for ZMM-dependant CO formation. HEI10 large foci - that mark CO sites in wild-type-form at a normal level in mlh1 and mlh3 mutants, but are inefficiently maturated into COs. Mutating the MUS81 nuclease in either mlh1 or mlh3 leads to chromosome fragmentation, which is suppressed by further mutating the zmm msh5. This suggests that in the absence of MutL{gamma}, recombination intermediates produced by ZMMs are resolved by MUS81, which does not ensure CO formation. Finally, CO interference is not affected in mlh1, which is compatible with a random sub-sampling of normally patterned CO sites. We conclude that AtMutL{gamma} imposes designated recombination intermediates to be resolved exclusively as COs, supporting the view that MutL{gamma} asymmetrically resolves double-Holliday junctions, yielding COs.

genetics↗

bioRxiv2024

Deciphering neuronal variability across states reveals dynamic sensory encoding

Influenced by factors such as brain states and behavior, neurons exhibit substantial response variability even to identical stimuli. Because these factors are non-stationary, they dynamically impact the fidelity of sensory processing. However, it remains unclear how their relative impact on neuronal variability evolves over time. To address this question, we designed an encoding model with latent states to partition visual cortical variability across three crucial categories of sources: internal brain dynamics, behavior, and external visual stimulus. Applying a hidden Markov model to the rhythmic patterns of cortical local field potentials, we consistently identified three distinct oscillation states. Each state revealed a unique variability profile and a consistent descending trend of stimulus modulation across the visual hierarchy. Regression models within each state revealed a dynamic composition of factors contributing to the observed spiking variability, with the primary influencing factor switching within seconds. In the state dominated by high-frequency oscillations, sensory inputs and behavior exerted the most influence on population dynamics. Conversely, internal brain activity explained most of the variance in the state dominated by low-frequency oscillations. This heterogeneity across states underscores the importance of partitioning variability over time, particularly when considering the dynamic influence of non-stationary factors on sensory processing.

neuroscience↗

bioRxiv2023

Complex sporulation-specific expression of transcription termination factor Rho highlights its involvement in Bacillus subtilis cell differentiation

Transcription termination factor Rho controls pervasive, mainly antisense, transcription initiated at cryptic signals or resulting from read-through at weak terminators in various bacterial species. In Bacillus subtilis, Rho is intricately involved in the regulation of phenomena associated with the adaptation to stationary phase and cell differentiation including the ultimate survival program of sporulation. While knockout or overexpression of the rho gene alters global transcription and modifies cell physiology, in wild-type B. subtilis cells, the reduction of Rho levels during the transition to stationary phase is necessary for both initiation and implementation of the sporulation program. However, the mechanisms that govern Rho expression throughout the cell cycle remain largely unknown. Here, we demonstrate that, besides the previously identified vegetative SigA-dependent promoter active during exponential growth, two distinct mechanisms ensure a spatiotemporal expression of the rho gene during sporulation. In the mother cell of the sporangium, rho expression occurs through the read-through transcription initiated at the distal SigH-dependent and Spo0A[~]P-regulated promoter of the spo0F gene. In the forespore, rho is transcribed from a genuine promoter recognized by the alternative sigma factor SigF. These regulatory elements compensate for the inactivation of SigA-dependent rho expression at the end of exponential growth and allow the critical "refueling" of Rho protein in both compartments of the sporangium. We show that altering rho expression in the mother cell or in the forespore affects differently the properties and the morphology of mature spores. Moreover, spores formed in the absence of Rho are impaired in their ability to revive under favorable growth conditions, exhibiting accelerated germination and slow outgrowth. Finally, we show that optimal outgrowth of the wild-type spores requires the expression of rho during spore maturation and additionally after spore germination.

microbiology↗

bioRxiv2023

Temporal stability of sex ratio distorter prevalence in natural populations of the isopod Armadillidium vulgare

AbstractIn the terrestrial isopod Armadillidium vulgare, many females produce progenies with female-biased sex ratios due to two feminizing sex ratio distorters (SRD): Wolbachia endosymbionts and a nuclear non-mendelian locus called the f element. To investigate the potential impact of these SRD on the evolution of host sex determination, we analyzed their temporal distribution in six A. vulgare populations sampled up to six times over 12 years, for a total of 29 time points. SRD distribution was heterogeneous among populations despite their close geographic locations, so that when one SRD was frequent in a population, the other SRD was rare. In contrast with spatial heterogeneity, our results overall did not reveal substantial temporal variability in SRD prevalence within populations, suggesting equilibria in SRD evolutionary dynamics may have been reached or nearly so. Temporal stability was also generally reflected in mitochondrial and nuclear variation. Nevertheless, in a population, a Wolbachia strain replacement coincided with changes in mitochondrial composition but no change in nuclear composition, thus constituting a typical example of mitochondrial sweep caused by endosymbiont rise in frequency. Rare incongruence between Wolbachia strains and mitochondrial haplotypes suggested the occurrence of intraspecific horizontal transmission, making it a biologically relevant parameter for Wolbachia evolutionary dynamics in A. vulgare. Overall, our results provide an empirical basis for future studies on SRD evolutionary dynamics in the context of multiple sex determination factors co-existing within a single species, to ultimately evaluate the impact of SRD on the evolution of host sex determination mechanisms and sex chromosomes.

evolutionary biology↗

bioRxiv2023

SHIELD: Skull-shaped hemispheric implants enabling large-scale-electrophysiology datasets in the mouse brain

To understand the neural basis of behavior, it is essential to measure spiking dynamics across many interacting brain regions. While new technologies, such as Neuropixels probes, facilitate multi-regional recordings, significant surgical and procedural hurdles remain for these experiments to achieve their full potential. Here, we describe a novel 3D-printed cranial-replacement implant (SHIELD) enabling electrophysiological recordings from distributed areas of the mouse brain. This skull-shaped implant is designed with customizable insertion holes, allowing dozens of cortical and subcortical structures to be recorded in a single mouse using repeated multi-probe insertions over many days. We demonstrate the procedures high success rate, biocompatibility, lack of adverse effects on behavior, and compatibility with imaging and optogenetics. To showcase the scientific utility of the SHIELD implant, we use multi-probe recordings to reveal novel insights into how alpha rhythms organize spiking activity across visual and sensorimotor networks. Overall, this method enables powerful large-scale electrophysiological measurements for the study of distributed brain computation.

neuroscience↗

bioRxiv2023

Coordinated changes in a cortical circuit sculpt effects of novelty on neural dynamics

Recent studies have found dramatic cell-type specific responses to stimulus novelty, highlighting the importance of analyzing the cortical circuitry at the cell-type specific level of granularity to understand brain function. Although initial work classified and characterized activity for each cell type, the specific alterations in cortical circuitry--particularly when multiple novelty effects interact--remain unclear. To address this gap, we employed a large-scale public dataset of electrophysiological recordings in the visual cortex of awake, behaving mice using Neuropixels probes and designed population network models to investigate the observed changes in neural dynamics in response to a combination of distinct forms of novelty. The model parameters were rigorously constrained by publicly available structural datasets, including multi-patch synaptic physiology and electron microscopy data. Our systematic optimization approach identified tens of thousands of model parameter sets that replicate the observed neural activity. Analysis of these solutions revealed generally weaker connections under novel stimuli, as well as a shift in the balance e between SST and VIP populations. Along with this, PV and SST populations experienced overall more excitatory influences compared to excitatory and VIP populations. Our results also highlight the role of VIP neurons in multiple aspects of visual stimulus processing and altering gain and saturation dynamics under novel conditions. In sum, our findings provide a systematic characterization of how the cortical circuit adapts to stimulus novelty by combining multiple rich public datasets.

neuroscience↗

bioRxiv2023

Small RNA regulation of an essential process induces bacterial resistance to aminoglycosides during oxidative stress

Fe-S clusters are essential cofactors involved in many reactions across all domains of life. In Escherichia coli and other enterobacteria, Fe-S cluster synthesis involves two machineries: Isc and Suf. While Isc functions as a housekeeping system, Suf is activated under stress conditions such as iron starvation or oxidative stress. Interestingly, cells functioning under Suf show reduced entry of aminoglycosides, leading to resistance to these antibiotics. The transcriptional regulator IscR, itself an Fe-S cluster containing protein, controls the transition between Isc and Suf machineries. Noteworthy, IscR has a critical impact on the virulence of various bacterial pathogens by regulating both Fe-S biogenesis and other pathways directly linked to host adaptation. Here, we discovered that two small regulatory RNAs (sRNAs), FnrS and OxyS, control iscR expression by base-pairing to the 5 UTR of the iscR mRNA. Remarkably, these sRNAs act in opposite ways and in opposite conditions: FnrS, expressed in anaerobiosis, represses the expression of iscR while OxyS, expressed during oxidative stress, activates it. Using an E. coli strain experiencing protracted oxidative stress, we further demonstrate that iscR expression is rapidly and significantly enhanced in the presence of OxyS. Strikingly, we further show that OxyS induces resistance to aminoglycosides during oxidative stress through this unexpected regulation of Fe-S clusters biogenesis, revealing a new role for this sRNA. Significance StatementThis study sheds light on the regulatory mechanisms controlling the synthesis of essential Fe-S clusters in bacteria, revealing unexpected roles for two small RNAs (FnrS and OxyS) in modulating the expression of the transcriptional regulator IscR. The findings suggest that this regulatory network could lead bacterial resistance to aminoglycoside antibiotics during oxidative stress, a condition associated with chronic infections. Ultimately, this work highlights the importance of understanding the intricate regulatory networks controlling bacterial metabolism and adaptation to stress, which could have significant implications for public health.

microbiology↗

bioRxiv2023

Critical factors for precise and efficient RNA cleavage by RNase Y in Staphylococcus aureus

Cellular processes require precise and specific gene regulation, in which continuous mRNA degradation is a major element. The mRNA degradation mechanisms should be able to degrade a wide range of different RNA substrates with high efficiency, but should at the same time be limited, to avoid killing the cell by elimination of all cellular RNA. RNase Y is a major endoribonuclease found in most Firmicutes, including Bacillus subtilis and Staphylococcus aureus. However, the molecular interactions that direct RNase Y to cleave the correct RNA molecules at the correct position remain unknown. In this work we have identified transcripts that are homologs in S. aureus and B. subtilis, and are RNase Y targets in both bacteria. Two such transcript pairs were used as models to show a functional overlap between the S. aureus and the B. subtilis RNase Y, which highlighted the importance of the nucleotide sequence of the RNA molecule itself in the RNase Y targeting process. Cleavage efficiency is driven by the primary nucleotide sequence immediately downstream of the cleavage site and base-pairing in a secondary structure a few nucleotides downstream. Cleavage positioning is roughly localised by the downstream secondary structure and fine-tuned by the nucleotide immediately upstream of the cleavage. The identified elements were sufficient for RNase Y-dependent cleavage, since the sequence elements from one of the model transcripts were able to convert an exogenous non-target transcript into a target for RNase Y. Author summaryIn order to correctly regulate the level of RNAs, bacteria require their RNA to be continuously synthesised and degraded. However, even related bacterial species can have different sets of ribonucleases, each with their own target criteria. Here we explore which sequence elements of an RNA are important for being targeted by the endoribonuclese RNase Y in the two bacteria, Staphylococcus aureus and Bacillus subtilis. We specifically examine the RNase Y dependent cleavage of two transcripts that have homologs in both bacteria. We identify a short single-stranded regions immediately downstream of the cleavage position can be modified to change the cleavage efficiency up to 20-fold. We furthermore discover that a secondary structure a few nucleotides downstream of the cleavage is required for cleavage and that the positioning of the cleavage can be modulated by moving this structure.

molecular biology↗

bioRxiv2023

Recurrent pattern completion drives the neocortical representation of sensory inference

When sensory information is incomplete or ambiguous, the brain relies on prior expectations to infer perceptual objects. Despite the centrality of this process to perception, the neural mechanism of sensory inference is not known. Illusory contours (ICs) are key tools to study sensory inference because they contain edges or objects that are implied only by their spatial context. Using cellular resolution, mesoscale two-photon calcium imaging and multi-Neuropixels recordings in the mouse visual cortex, we identified a sparse subset of neurons in the primary visual cortex (V1) and higher visual areas that respond emergently to ICs. We found that these highly selective IC-encoders mediate the neural representation of IC inference. Strikingly, selective activation of these neurons using two-photon holographic optogenetics was sufficient to recreate IC representation in the rest of the V1 network, in the absence of any visual stimulus. This outlines a model in which primary sensory cortex facilitates sensory inference by selectively strengthening input patterns that match prior expectations through local, recurrent circuitry. Our data thus suggest a clear computational purpose for recurrence in the generation of holistic percepts under sensory ambiguity. More generally, selective reinforcement of top-down predictions by pattern-completing recurrent circuits in lower sensory cortices may constitute a key step in sensory inference.

neuroscience↗

bioRxiv2023

The endoplasmic reticulum stress sensor IRE1 regulates collagen secretion through the enforcement of the proteostasis factor P4HB/PDIA1 contributing to liver damage and fibrosis

Collagen is one the most abundant proteins and the main cargo of the secretory pathway, contributing to hepatic fibrosis and cirrhosis due to excessive deposition of extracellular matrix. Here we investigated the possible contribution of the unfolded protein response, the main adaptive pathway that monitors and adjusts the protein production capacity at the endoplasmic reticulum, to collagen biogenesis and liver disease. Genetic ablation of the ER stress sensor IRE1 reduced liver damage and diminished collagen deposition in models of liver fibrosis triggered by carbon tetrachloride (CCl4) administration or by high fat diet. Proteomic and transcriptomic profiling identified the prolyl 4-hydroxylase (P4HB, also known as PDIA1), which is known to be critical for collagen maturation, as a major IRE1-induced gene. Cell culture studies demonstrated that IRE1 deficiency results in collagen retention at the ER and altered secretion, a phenotype rescued by P4HB overexpression. Taken together, our results collectively establish a role of the IRE1/P4HB axis in the regulation of collagen production and its significance in the pathogenesis of various disease states.

cell biology↗

bioRxiv2023

A high-resolution view of RNA endonuclease cleavage in Bacillus subtilis

RNA endonucleases are the rate-limiting initiator of decay for many bacterial mRNAs. However, the positions of cleavage and their sequence determinants remain elusive even for the well-studied Bacillus subtilis. Here we present two complementary approaches - transcriptome-wide mapping of endoribonucleolytic activity and deep mutational scanning of RNA cleavage sites - that reveal distinct rules governing the specificity among B. subtilis endoribonucleases. Detection of RNA terminal nucleotides in both 5'- and 3'-exonuclease-deficient cells revealed >103 putative endonucleolytic cleavage sites with single-nucleotide resolution. We found a surprisingly weak consensus for RNase Y targets, a contrastingly strong primary sequence motif for EndoA targets, and long-range intramolecular secondary structures for RNase III targets. Deep mutational analysis of RNase Y cleavage sites showed that the specificity is governed by many disjointed sequence features, each with mild contributions. Our results highlight the delocalized nature of mRNA stability determinants and provide a strategy for elucidating endoribonuclease specificity in vivo.

molecular biology↗

bioRxiv2023

ZEB1 controls a lineage-specific transcriptional program essential for melanoma cell state transitions

Cell plasticity sustains intra-tumor heterogeneity and treatment resistance in melanoma. Deciphering the transcriptional mechanisms governing reversible phenotypic transitions between proliferative/differentiated and invasive/stem-like states is required. Expression of the ZEB1 transcription factor is frequently activated in melanoma, where it fosters adaptive resistance to targeted therapies. Here, we performed a genome-wide characterization of ZEB1 transcriptional targets, by combining ChIP-sequencing and RNA-sequencing, upon phenotype switching in melanoma models. We identified and validated ZEB1 binding peaks in the promoter of key lineage-specific genes crucial for melanoma cell identity. Mechanistically, ZEB1 negatively regulates SOX10-MITF dependent proliferative/melanocytic programs and positively regulates AP-1 driven invasive and stem-like programs. Comparative analyses with breast carcinoma cells revealed lineage-specific ZEB1 binding, leading to the design of a more reliable melanoma-specific ZEB1 regulon. We then developed single-cell spatial multiplexed analyses to characterize melanoma cell states intra-tumoral heterogeneity in human melanoma samples. Combined with scRNA-Seq analyses, our findings confirmed increased ZEB1 expression in Neural-Crest-like cells and mesenchymal cells, underscoring its significance in vivo in both populations. Overall, our results define ZEB1 as a major transcriptional regulator of cell states transitions and provide a better understanding of lineage-specific transcriptional programs sustaining intra-tumor heterogeneity in melanoma. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=170 SRC="FIGDIR/small/526467v2_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@6c487eorg.highwire.dtl.DTLVardef@10b52aborg.highwire.dtl.DTLVardef@60821eorg.highwire.dtl.DTLVardef@1fe9f90_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2023

Targeting the cell and non-cell autonomous regulation of 47S synthesis by GCN2 in colon cancer.

Nutrient availability is a key determinant of tumor cell behavior. While nutrient-rich conditions favor proliferation and tumor growth, scarcity, and particularly glutamine starvation, promotes cell dedifferentiation and chemoresistance. Here, linking ribosome biogenesis plasticity with tumor cell fate, we uncover that the amino acid sensor GCN2 represses the expression of the precursor of ribosomal RNA, 47S, under metabolic stress. We show that blockade of GCN2 triggers cell death by an irremediable nucleolar stress and subsequent TP53-mediated apoptosis in patient-derived models of colon adenocarcinoma (COAD). In nutrient-rich conditions, GCN2 activity supports cell proliferation through the transcription stimulation of 47S rRNA, independently of the canonical ISR axis. However, impairment of GCN2 activity prevents nuclear translocation of the methionyl tRNA synthetase (MetRS) underlying the generation of a nucleolar stress, mTORC1 inhibition and autophagy induction. Inhibition of the GCN2-MetRS axis drastically improves the cytotoxicity of RNA pol I inhibitors, including the first-line chemotherapy oxaliplatin, on patient-derived COAD tumoroids. Our data thus reveal that GCN2 differentially controls the ribosome biogenesis according the nutritional context. Furthermore, pharmacological co-inhibition of the two GCN2 branches and the RNA pol I activity may represent a valuable strategy for elimination of proliferative and metabolically-stressed COAD cell.

cancer biology↗