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The colibactin-producing Escherichia coli alters the tumor microenvironment to immunosuppressive lipid overload facilitating colorectal cancer progression and chemoresistance
No full textInternational audienceIntratumoral bacteria flexibly contribute to cellular and molecular tumor heterogeneity for supporting cancer recurrence through poorly understood mechanisms. Using spatial metabolomic profiling technologies and 16SrRNA sequencing, we herein report that right-sided colorectal tumors are predominantly populated with Colibactin-producing Escherichia coli (CoPEC) that are locally establishing a high-glycerophospholipid microenvironment with lowered immunogenicity. It coincided with a reduced infiltration of CD8+ T lymphocytes that produce the cytotoxic cytokines IFN-γ where invading bacteria have been geolocated. Mechanistically, the accumulation of lipid droplets in infected cancer cells relied on the production of colibactin as a measure to limit genotoxic stress to some extent. Such heightened phosphatidylcholine remodeling by the enzyme of the Land’s cycle supplied CoPEC-infected cancer cells with sufficient energy for sustaining cell survival in response to chemotherapies. This accords with the lowered overall survival of colorectal patients at stage III-IV who were colonized by CoPEC when compared to patients at stage I-II. Accordingly, the sensitivity of CoPEC-infected cancer cells to chemotherapies was restored upon treatment with an acyl-CoA synthetase inhibitor. By contrast, such metabolic dysregulation leading to chemoresistance was not observed in human colon cancer cells that were infected with the mutant strain that did not produce colibactin (11G5∆ClbQ). This work revealed that CoPEC locally supports an energy trade-off lipid overload within tumors for lowering tumor immunogenicity. This may pave the way for improving chemoresistance and subsequently outcome of CRC patients who are colonized by CoPEC
Convolutional Spiking Neural Network Simulator (CSNN)
No full textA simulator dedicated to run multi-layered spiking neural network in C++ . This tool is designed to optimize the time simulation of such architectures on CPU, by providing SIMD implementation of spiking convolution and pooling layer. Moreover, every experimentation configuration is automatically saved in a file, which helps to keep a track of previous results, and allows to easily reload past experimentation
The Eclectic User Experience of Combined On-Screen and On-Wrist Vibrotactile Feedback in Touchscreen Input
No full textInternational audienc
Widening exposome exploration by means of complementary HRMS analytical platforms: use case on pesticide exposure
No full textInternational audienceHuman exposure to food and environmental contaminants (such as pesticides) is generally estimated by indirect methods. Targeted bio-monitoring is a way to assess the internal exposure on a limited number of substances, needing large sample amounts for analyses as rigorous and sensitive as possible. Thus, the human health risks associated with multi-exposure to complex mixtures currently remain under-explored.In this context, the SCREENPEST project aims at providing a unified methodology for large-scale characterisation of human internal exposure to pesticides, via a "suspect profiling" approach, using urine
Acidic Growth Conditions Promote Epithelial-to-Mesenchymal Transition to Select More Aggressive PDAC Cell Phenotypes In Vitro
No full textInternational audiencePancreatic Ductal Adenocarcinoma (PDAC) is characterized by an acidic microenvironment, which contributes to therapeutic failure. So far there is a lack of knowledge with respect to the role of the acidic microenvironment in the invasive process. This work aimed to study the phenotypic and genetic response of PDAC cells to acidic stress along the different stages of selection. To this end, we subjected the cells to short- and long-term acidic pressure and recovery to pHe 7.4. This treatment aimed at mimicking PDAC edges and consequent cancer cell escape from the tumor. The impact of acidosis was assessed for cell morphology, proliferation, adhesion, migration, invasion, and epithelial–mesenchymal transition (EMT) via functional in vitro assays and RNA sequencing. Our results indicate that short acidic treatment limits growth, adhesion, invasion, and viability of PDAC cells. As the acid treatment progresses, it selects cancer cells with enhanced migration and invasion abilities induced by EMT, potentiating their metastatic potential when re-exposed to pHe 7.4. The RNA-seq analysis of PANC-1 cells exposed to short-term acidosis and pHe-selected recovered to pHe 7.4 revealed distinct transcriptome rewiring. We describe an enrichment of genes relevant to proliferation, migration, EMT, and invasion in acid-selected cells. Our work clearly demonstrates that upon acidosis stress, PDAC cells acquire more invasive cell phenotypes by promoting EMT and thus paving the way for more aggressive cell phenotypes
Les cahiers de la SFSIC -18- EDITO
No full textInternational audienceLe présent numéro, loin d’échapper au questionnement des grands enjeux et efets du numérique, met l’accent sur denouvelles recherches ou projets pédagogiques menés par des collègues dans le champ des sciences de l’information et de la communication. Il se structure en 4 grands volets : Questions de recherches,Formation, Mondes professionnels, Carte blanche aux doctorant
Involvement of the NLRC5 / MHC class I axis in human colorectal cancer immune surveillance
No full textInternational audienceMost of patients with colorectal cancer (CRC) without microsatellite instability fail torespond to immune checkpoint blockade (ICB) through poorly understood changes in thetumor microenvironment. Recently, we provided evidence that the tonus of tumor infiltratingT lymphocytes (TILs) is associated to the intra-tumoral activity of Caspase-1 (doi:10.3390/cancers13020189). Bulk RNA-seq analysis of CRC revealed a greater expression level of NLRfamily CARD domain containing 5 (NLRC5) in tumors with a detectable Caspase-1 activity.Given that NLRC5 is a regulator of major histocompatibility complex class I (MHC-I) antigenpresentation, we postulated that NLRC5 may modulate cancer immune surveillance andresponsiveness to ICB. We thereby evaluated the significance of the intratumoral changesin NLRC5 expression in several cohorts of patients. We show that NLRC5 is a favorableprognostic factor of overall survival in 100 CRC and of responsiveness to ICB in 45 metastaticCRC. In agreement, NLRC5 expression in KRAS wild type CRC is of better prognosis andpositively correlates with PD1/PD-L1 axis. Conversely, a negative correlation is observedbetween PRMT5, an epigenetic modifier that represses NLRC5 expression, and PD-1/PD-L1axis. Finally, functional studies using co-cultures of TILs isolated from CRC fragments andcolonic cancer cell lines show that enforced expression of NLRC5 in tumor cells enhancesthe cytotoxic activity of CD8+ TILs (cytokine production, degranulation), via a MHC-I-dependent mechanism. Overall, our findings suggest that NLRC5 could be a valuablebiomarker in CRC and that increasing the NLRC5/MHC-I axis in tumor cells could enhanceanti-tumor immunity and immunotherapeutic responses
NALCN ‐mediated sodium influx confers metastatic prostate cancer cell invasiveness
No full textInternational audienceThere is growing evidence that ion channels are critically involved in cancer cell invasiveness and metastasis. However, the molecular mechanisms of ion signaling promoting cancer behavior are poorly understood and the complexity of the underlying remodeling during metastasis remains to be explored. Here, using a variety of in vitro and in vivo techniques, we show that metastatic prostate cancer cells acquire a specific Na+ /Ca2+ signature required for persistent invasion. We identify the Na+ leak channel, NALCN, which is overexpressed in metastatic prostate cancer, as a major initiator and regulator of Ca2+ oscillations required for invadopodia formation. Indeed, NALCN-mediated Na+ influx into cancer cells maintains intracellular Ca2+ oscillations via a specific chain of ion transport proteins including plasmalemmal and mitochondrial Na+ /Ca2+ exchangers, SERCA and store-operated channels. This signaling cascade promotes activity of the NACLN-colocalized proto-oncogene Src kinase, actin remodeling and secretion of proteolytic enzymes, thus increasing cancer cell invasive potential and metastatic lesions in vivo. Overall, our findings provide new insights into an ion signaling pathway specific for metastatic cells where NALCN acts as persistent invasion controller
