Biology subjects

Roger, E.

Publications and source records attributed to Roger, E..

9 recordsLinked to original sources

bioRxiv2025

Exploiting TGF-β-mediated Stromal Programming in Homologous Recombination-Deficient Pancreatic Cancer

The tumor microenvironment (TME) actively contributes to pancreatic ductal adenocarcinoma (PDAC) pathogenesis through dynamic bidirectional tumor-stroma interactions. Here, we demonstrate that homologous recombination-defective (HRD) tumor epithelium reprograms the TME in a genotype-specific manner to enhance cancer aggressiveness. Using genetically engineered mouse models, pancreatic stellate cell (PSC) and cancer-associated fibroblast (CAF) co-culture systems, single-nucleus multiomics, and human PDAC models, we show that tumoral loss of ATM serine/threonine kinase drives CAFs toward SMA+ myofibroblastic differentiation, independently of P53 status. These myCAFs, in turn, promote cancer aggressiveness and chemoresistance. Mechanistically, ATM deficiency increases reactive oxygen species and contractility signaling, enhancing TGF-{beta}1 secretion. Pharmacological TGF-{beta} inhibition reverses myCAF differentiation, sensitizes tumors to chemotherapy, and impairs tumor progression in both murine and human ATM-null models. Our findings reveal that ATM-deficient tumors shape a cancer-promoting niche via TGF-{beta} signaling and identify dual targeting of intrinsic and extrinsic vulnerabilities as a promising precision oncology strategy. SIGNIFICANCEHRD pancreatic cancers reprogram the tumor microenvironment in a genotype-specific manner through TGF-{beta}-driven myCAF-enrichment. Targeting this stromal axis alongside platinum-based chemotherapy improves therapeutic efficacy in ATM-deficient models. These findings highlight the need to integrate epithelial genotype and stromal context for truly personalized treatment strategies in PDAC.

cancer biology↗

bioRxiv2025

Pancreatic cancer patient-derived organoids capture therapy response and tumor evolution

Patient-derived organoids (PDOs) reflect parental tumor features and may represent promising avatars for prognosticating drug response. Here, we recruited 169 patients with pancreatic cancer (PC) and established a living biobank including 83 pharmacotyped PDOs isolated from primary and metastatic, treatment-naive and pretreated PCs. In a core facility setting, the pharmacotyping success rate was 61.5%, with an unmet turnaround time of 32 days. Forty-six patients who underwent a total of 94 therapeutic lines were analyzed, resulting in a pharmacotyping-patient response matching rate of 73.4%. Sensitivity, specificity, positive and negative predictive values were 85.0%, 64.8%, 64.2%, and 85.4%, respectively. Tracing clonal evolution in longitudinal biopsies uncovered therapy-induced genetic alterations and single-nucleus multiomics identified transcriptomic and epigenetic changes associated with abnormal FGF signaling during treatment in one particular tracked study case. Our findings highlight the potential of PDOs as robust tools for drug response prediction and patient modeling to advance functional precision medicine.

cancer biology↗

bioRxiv2024

Dynamics of White Matter Architecture in Lexical Production among Middle-Aged Adults

This study aimed to elucidate the white matter changes associated with lexical production (LP) difficulties that typically emerge in middle age, resulting in increased naming latencies. To delay the onset of LP decline, middle-aged adults may rely on domain-general (DG) and language-specific (LS) compensatory mechanisms as proposed by the LARA model (Lexical Access and Retrieval in Aging). However, our knowledge of the white matter changes supporting these mechanisms remains incomplete. Based on a sample of 155 middle-aged adults from the CAMCAN cohort, we combined dimensionality reduction techniques with multivariate statistical methods to jointly examine the relationships between diffusion-weighted imaging and LP-related neuropsychological data. Our findings (i) show that midlife constitutes a pivotal period marked by a discontinuity in brain structure within distributed networks within dorsal, ventral, and anterior cortico-subcortical pathways, and (ii) reveal that this discontinuity signals a neurocognitive transition around age 53-54, marking the onset of LP decline. Indeed, our results propose that middle-aged adults may initially adopt a "semantic strategy" to compensate for initial LP challenges. Still, this strategy may be compromised when late middle-aged adults (age 55-60) lose the ability to exert cognitive control over semantic representations (i.e., reduced semantic control). In summary, our study advances our comprehension of brain structure changes that underpin the neurocognitive profile of LP in middle age. Specifically, we underscore the importance of considering the interplay between DG and LS processes when studying the trajectory of LP performance in healthy aging. Furthermore, these findings offer valuable insights into identifying predictive biomarkers related to the compensatory dynamics observed in midlife, which can help understand language-related neurodegenerative pathologies. HighlightsO_LIMidlife constitutes a pivotal period characterized by a discontinuity in brain structure. C_LIO_LIEarly middle-aged adults (age 45-55) adopt a "semantic strategy" to facilitate semantic access and sustain lexical production (LP) performances. C_LIO_LILate middle-aged adults (age 55-60) gradually lose the ability to exert cognitive control over semantic representations, marking the onset of LP decline. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=105 SRC="FIGDIR/small/579645v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@85346dorg.highwire.dtl.DTLVardef@13515b7org.highwire.dtl.DTLVardef@24a1fforg.highwire.dtl.DTLVardef@1078f4c_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

When Age Tips the Balance: a Dual Mechanism Affecting Hemispheric Specialization for Language

Aging leads to neuroadaptations, often reducing specificity in functional brain responses. However, the extent to which functional specialization of brain hemispheres in the Language-and-Memory Network regions changes with adulthood remains unclear. In a cohort of healthy adults, we provide evidence that aging is linked to shifts in the cortical organizations lateralization, unveiling two age-related asymmetry patterns. The first pattern indicates a lateralization shift in language regions, with aging rendering language functions more bilateral. The second pattern reveals increased specialization in memory regions within the left hemisphere as we age. Manifesting around midlife, these shifts correlate with declines in language production performance. Our findings offer new insights into how functional brain asymmetries impact language proficiency and underscore brain plasticity in aging, providing a dynamic view of the aging brains functional architecture.

neuroscience↗

bioRxiv2023

The PP1 phosphatase exhibits pleiotropic roles controlling both the tachyzoite cell cycle and amylopectin-steady state levels in Toxoplasma gondii.

Virulence of apicomplexan parasites is based on their ability to divide rapidly to produce significant biomass. The regulation of their cell-cycle is therefore key to their pathogenesis. Phosphorylation is a crucial post-transcriptional modification that regulates many aspects of the eucaryotic cell cycle. The phosphatase PP1 is known to play a major role in the phosphorylation balance in eukaryotes. We explored the role of TgPP1 during the cell cycle of the tachyzoite form of the apicomplexan parasite Toxoplasma gondii. Using a conditional mutant strain, we show that TgPP1 regulates many aspects of the cell cycle including the proper assembly of the daughter cells inner membrane complex (IMC), the segregation of organelles and nuclear division. Unexpectedly, depletion of TgPP1 also results in the accumulation of amylopectin, a storage polysaccharide that is normally found in the latent bradyzoite form of the parasite. Using transcriptomics and phosphoproteomics, we show that TgPP1 mainly acts through post-transcriptional mechanisms by dephosphorylating target proteins including IMC proteins. TgPP1 also dephosphorylate a protein bearing a starch binding domain. Mutagenesis analysis reveals that the targeted phospho-sites are linked to the ability of the parasite to regulate amylopectin steady-state levels. Therefore, we show that TgPP1 has pleiotropic roles during the tachyzoite cell cycle regulation, but also regulates amylopectin accumulation.

microbiology↗

bioRxiv2022

Unraveling the functional attributes of the language connectome: crucial subnetworks, flexibility and variability.

Language processing is a highly integrative function, intertwining linguistic operations (processing the language code intentionally used for communication) and extra-linguistic processes (e.g., attention monitoring, predictive inference, long-term memory). This synergetic cognitive architecture requires a distributed and specialized neural substrate. Brain systems have mostly been examined at rest. However, task-related functional connectivity provides additional and valuable information about how information is processed when various cognitive states are involved. We gathered thirteen language fMRI tasks in a unique database of one hundred and fifty neurotypical adults (InLang database). The tasks were designed to assess a wide range of linguistic processes and subprocesses. From this database, we applied network theory as a computational tool to model the task-related functional connectome of language (LANG). The organization of this data-driven neurocognitive atlas of language is examined at multiple levels, uncovering its major components (or crucial subnetworks) and its anatomical and functional correlates. Furthermore, we estimate its reconfiguration as a function of linguistic demand (flexibility), or several factors such as age or gender (variability). By accounting for the multifaceted nature of language and modulating factors, this study can contribute to enrich and refine existing neurocognitive models of language. The LANG atlas can also be considered as a reference for comparative or clinical studies, involving a variety of patients and conditions.

neuroscience↗

bioRxiv2021

Primary brain cell infection by Toxoplasma gondii reveals the extent and dynamics of parasite differentiation and impact on neuron biology.

Toxoplasma gondii is a eukaryotic parasite that forms latent cysts in the brain of immunocompetent individuals. The latent parasite infection of the immune-privileged central nervous system is linked to most complications. With no drug currently available to eliminate the latent cysts in the brain of infected hosts, the consequences of neurons long-term infection are unknown. It has long been known that T. gondii specifically differentiates into a latent form (bradyzoite) in neurons, but how the infected neuron responds to the infection remains to be elucidated. We have established a new in vitro model resulting in the production of mature bradyzoite cysts in brain cells. Using dual, host and parasite RNA-seq, we characterized the dynamics of differentiation of the parasite, revealing the involvement of key pathways in this process. Moreover, we identified how the infected brain cells responded to the parasite infection revealing the drastic changes that take place. We showed that neuronal-specific pathways are strongly affected, with synapse signaling being particularly affected, especially glutamatergic synapse signaling. The establishment of this new in vitro model allows investigating both the dynamics of parasite differentiation and the specific response of neurons to the long-term infection by this parasite.

microbiology↗

bioRxiv2020

m6A RNA methylation regulates the fate of endogenous retroviruses

Endogenous retroviruses (ERVs) are abundant and heterogenous groups of integrated retroviral sequences that impact genome regulation and cell physiology throughout their RNA-centered life cycle1. Failure to repress ERVs is associated with cancer, infertility, senescence and neurodegenerative diseases2-4. Here, using an unbiased genome-scale CRISPR knockout screen in mouse embryonic stem cells, we identify m6A RNA methylation as a novel means of ERV restriction. Methylation of ERV mRNAs is catalyzed by the complex of methyltransferase-like METTL3/METTL145 proteins whose depletion, along with their accessory subunits, WTAP and ZC3H13, led to increased mRNA abundance of Intracisternal A-particles (IAPs) and related ERVK elements specifically, by targeting their 5UTR region. Using controlled auxin-dependent degradation of the METTL3/METTL14 enzymatic complex, we showed that IAP mRNA and protein abundance is dynamically and inversely correlated with m6A catalysis. By monitoring mRNA degradation rates upon METTL3/14 double degron, we further proved that m6A methylation destabilizes IAP transcripts. Finally, similarly to m6A writers, triple knockout of the m6A readers YTHDF1, DF2 and DF36 increased IAP mRNA abundance. This study sheds light onto a novel function of RNA methylation in protecting cellular integrity by clearing reactive ERV-derived RNA species, which may be especially important when transcriptional silencing is less stringent.

cell biology↗

bioRxiv2019

Interactive mapping of language and memory with the GE2REC protocol

Previous studies have highlighted the importance of considering cognitive functions in a dynamic and interactive perspective and multiple evidence was brought for a language and memory interaction. In this study performed in healthy participants, we developed a new protocol entitled GE2REC that interactively accesses the neural representation of language-and-memory network. This protocol consists of three runs related to each other, providing a link between tasks, in order to assure an interactive measure of linguistic and episodic memory processes. GE2REC consists of a sentence generation (GE) in auditory modality and two recollecting (2REC) memory tasks, one recognition performed in visual modality, and another one recall performed in auditory modality. Its efficiency was evaluated in 20 healthy volunteers using a 3T MR imager. Our results corroborate the ability of GE2REC to robustly activate a fronto-temporo-parietal language network as well as temporal mesial, prefrontal and parietal cortices during encoding and recognition. GE2REC is useful because: (a) requires simultaneous and interactive language-and-memory processes and jointly maps their neural basis; (b) explores encoding and retrieval, managing to elicit activation of mesial temporal structures; (c) is short and easy to perform, hence being suitable for more restrictive settings, and (d) has an ecological dimension of tasks and stimuli. Overall, GE2REC can provide valuable information in terms of the practical foundation of exploration language and memory interconnection.

neuroscience↗