Capture at the single cell level of metabolic modules distinguishing aggressive and indolent glioblastoma cells

International audienceGlioblastoma cell ability to adapt their functioning to microenvironment changes is a source of the extensive intra-tumor heterogeneity characteristic of this devastating malignant brain tumor. A systemic view of the metabolic pathways underlying glioblastoma cell functioning states is lacking. We analyzed public single cell RNA-sequencing data from glioblastoma surgical resections, which offer the closest available view of tumor cell heterogeneity as encountered at the time of patients' diagnosis. Unsupervised analyses revealed that information dispersed throughout the cell transcript repertoires encoded the identity of each tumor and masked information related to cell functioning states. Data reduction based on an experimentally-defined signature of transcription factors overcame this hurdle. It allowed cell grouping according to their tumorigenic potential, regardless of their tumor of origin. The approach relevance was validated using independent datasets of glioblastoma cell and tissue transcriptomes, patient-derived cell lines and orthotopic xenografts. Overexpression of genes coding for amino acid and lipid metabolism enzymes involved in anti-oxidative, energetic and cell membrane processes characterized cells with high tumorigenic potential. Modeling of their expression network highlighted the very long chain polyunsaturated fatty acid synthesis pathway at the core of the network. Expression of its most downstream enzymatic component, ELOVL2, was associated with worsened patient survival, and required for cell tumorigenic properties in vivo. Our results demonstrate the power of signature-driven analyses of single cell transcriptomes to obtain an integrated view of metabolic pathways at play within the heterogeneous cell landscape of patient tumors

Cellular senescence in malignant cells promotes tumor progression in mouse and patient Glioblastoma

Abstract Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, yet it remains refractory to systemic therapy. Elimination of senescent cells has emerged as a promising new treatment approach against cancer. Here, we investigated the contribution of senescent cells to GBM progression. Senescent cells were identified in patient and mouse GBMs. Partial removal of p16 Ink4a -expressing malignant senescent cells, which make up less than 7 % of the tumor, modified the tumor ecosystem and improved the survival of GBM-bearing mice. By combining single cell and bulk RNA sequencing, immunohistochemistry and genetic knockdowns, we identified the NRF2 transcription factor as a determinant of the senescent phenotype. Remarkably, our mouse senescent transcriptional signature and underlying mechanisms of senescence are conserved in patient GBMs, in whom higher senescence scores correlate with shorter survival times. These findings suggest that senolytic drug therapy may be a beneficial adjuvant therapy for patients with GBM

BMP signalling directs a fibroblast-to-myoblast conversion at the connective tissue/muscle interface to pattern limb muscles

Posté sur BioRxiv le 21 juillet 2020Positional information driving limb muscle patterning is contained in lateral plate mesoderm-derived tissues, such as tendon or muscle connective tissue but not in myogenic cells themselves. The long-standing consensus is that myogenic cells originate from the somitic mesoderm, while connective tissue fibroblasts originate from the lateral plate mesoderm. We challenged this model using cell and genetic lineage tracing experiments in birds and mice, respectively, and identified a subpopulation of myogenic cells at the muscle tips close to tendons originating from the lateral plate mesoderm and derived from connective tissue gene lineages. Analysis of single-cell RNA-sequencing data obtained from limb cells at successive developmental stages revealed a subpopulation of cells displaying a dual muscle and connective tissue signature, in addition to independent muscle and connective tissue populations. Active BMP signalling was detected in this junctional cell sub-population and at the tendon/muscle interface in developing limbs. BMP gain- and loss-of-function experiments performed in vivo and in vitro showed that this signalling pathway regulated a fibroblast-to-myoblast conversion. We propose that localised BMP signalling converts a subset of lateral plate mesoderm-derived fibroblasts to a myogenic fate and establishes a boundary of fibroblast-derived myonuclei at the muscle/tendon interface to control the muscle pattern during limb development

Unexpected contribution of fibroblasts to muscle lineage as a mechanism for limb muscle patterning

International audiencePositional information driving limb muscle patterning is contained in connective tissue fibroblasts but not in myogenic cells. Limb muscles originate from somites, while connective tissues originate from lateral plate mesoderm. With cell and genetic lineage tracing we challenge this model and identify an unexpected contribution of lateral plate-derived fibroblasts to the myogenic lineage, preferentially at the myotendinous junction. Analysis of single-cell RNA-sequencing data from whole limbs at successive developmental stages identifies a population displaying a dual muscle and connective tissue signature. BMP signalling is active in this dual population and at the tendon/muscle interface. In vivo and in vitro gain-and loss-of-function experiments show that BMP signalling regulates a fibroblast-tomyoblast conversion. These results suggest a scenario in which BMP signalling converts a subset of lateral plate mesoderm-derived cells to a myogenic fate in order to create a boundary of fibroblast-derived myonuclei at the myotendinous junction that controls limb muscle patterning

Glioblastoma cell motility depends on enhanced oxidative stress coupled with mobilization of a sulfurtransferase

International audienceAbstract Cell motility is critical for tumor malignancy. Metabolism being an obligatory step in shaping cell behavior, we looked for metabolic weaknesses shared by motile cells across the diverse genetic contexts of patients’ glioblastoma. Computational analyses of single-cell transcriptomes from thirty patients’ tumors isolated cells with high motile potential and highlighted their metabolic specificities. These cells were characterized by enhanced mitochondrial load and oxidative stress coupled with mobilization of the cysteine metabolism enzyme 3-Mercaptopyruvate sulfurtransferase (MPST). Functional assays with patients’ tumor-derived cells and -tissue organoids, and genetic and pharmacological manipulations confirmed that the cells depend on enhanced ROS production and MPST activity for their motility. MPST action involved protection of protein cysteine residues from damaging hyperoxidation. Its knockdown translated in reduced tumor burden, and a robust increase in mice survival. Starting from cell-by-cell analyses of the patients’ tumors, our work unravels metabolic dependencies of cell malignancy maintained across heterogeneous genomic landscapes

The EUREC4A-Ocean/Atmosphere campaign: status

International audienceThe ocean fine scale (from the mesoscale to the submesoscale) is susceptible to impact air-sea exchange and has an integral effect on the large scale atmosphere and ocean dynamics. Many recent advances in understanding underlying processes have been obtained from modeling efforts and only few in-situ observational studies exist one of them being the EUREC4A-OA/ATOMIC campaign that was added to the EUREC4A atmospheric campaign. This experiment took place in January-February 2020 in the Northwest Tropical Atlantic Ocean with the aim to collect synchronized ocean and atmosphere data to improve our understanding of the role of fine scale processes in the internal ocean dynamics and air-sea interaction.Four oceanographic vessels, coordinated with air-borne observations and autonomous ocean platforms (underwater gliders, Saildrones, drifters), simultaneously acquired ocean and atmosphere data east of the island of Barbados and further south, up to the border of French Giuana. This way, ocean and atmospheric data was acquired in two contrasting regions: (1) the Trade wind region and (2) a region filled with mesoscale eddies. Operations allowed investigating upper ocean processes from small to mesoscale and from sub-diurnal to monthly.A variety of mesoscale eddies were crossed with diverse characteristics, ranging from shallow cyclonic and anticyclonic eddies to the deep reaching structures. Some of these eddies, and in particular North Brazil Rings, have been previously observed and described in dedicated oceanographic experiments. Nonetheless, the EUREC4A-OA/ATOMIC campaign brings in new details about the vertical structure, the dynamics and the potential impact on air-sea interactions of these mesoscale features.With the various observing platforms it was possible to sample the upper-ocean in great detail, resolving frontal scales and stratification. For example, the remnants of the Amazon plume, flowing northward along the shelf-break and being advected far offshore though NBC rings, create a rich variety of submesoscale fronts and a strong barrier layer impacting air-sea exchange of heat and momentum. The ongoing analyses on the ocean dynamics regional and local structures and specifics of air-sea interaction will be highlighted in this presentation

The EUREC4A-Ocean/Atmosphere campaign: status

International audienceThe ocean fine scale (from the mesoscale to the submesoscale) is susceptible to impact air-sea exchange and has an integral effect on the large scale atmosphere and ocean dynamics. Many recent advances in understanding underlying processes have been obtained from modeling efforts and only few in-situ observational studies exist one of them being the EUREC4A-OA/ATOMIC campaign that was added to the EUREC4A atmospheric campaign. This experiment took place in January-February 2020 in the Northwest Tropical Atlantic Ocean with the aim to collect synchronized ocean and atmosphere data to improve our understanding of the role of fine scale processes in the internal ocean dynamics and air-sea interaction.Four oceanographic vessels, coordinated with air-borne observations and autonomous ocean platforms (underwater gliders, Saildrones, drifters), simultaneously acquired ocean and atmosphere data east of the island of Barbados and further south, up to the border of French Giuana. This way, ocean and atmospheric data was acquired in two contrasting regions: (1) the Trade wind region and (2) a region filled with mesoscale eddies. Operations allowed investigating upper ocean processes from small to mesoscale and from sub-diurnal to monthly.A variety of mesoscale eddies were crossed with diverse characteristics, ranging from shallow cyclonic and anticyclonic eddies to the deep reaching structures. Some of these eddies, and in particular North Brazil Rings, have been previously observed and described in dedicated oceanographic experiments. Nonetheless, the EUREC4A-OA/ATOMIC campaign brings in new details about the vertical structure, the dynamics and the potential impact on air-sea interactions of these mesoscale features.With the various observing platforms it was possible to sample the upper-ocean in great detail, resolving frontal scales and stratification. For example, the remnants of the Amazon plume, flowing northward along the shelf-break and being advected far offshore though NBC rings, create a rich variety of submesoscale fronts and a strong barrier layer impacting air-sea exchange of heat and momentum. The ongoing analyses on the ocean dynamics regional and local structures and specifics of air-sea interaction will be highlighted in this presentation

The EUREC4A-Ocean/Atmosphere campaign: status

International audienceThe ocean fine scale (from the mesoscale to the submesoscale) is susceptible to impact air-sea exchange and has an integral effect on the large scale atmosphere and ocean dynamics. Many recent advances in understanding underlying processes have been obtained from modeling efforts and only few in-situ observational studies exist one of them being the EUREC4A-OA/ATOMIC campaign that was added to the EUREC4A atmospheric campaign. This experiment took place in January-February 2020 in the Northwest Tropical Atlantic Ocean with the aim to collect synchronized ocean and atmosphere data to improve our understanding of the role of fine scale processes in the internal ocean dynamics and air-sea interaction.Four oceanographic vessels, coordinated with air-borne observations and autonomous ocean platforms (underwater gliders, Saildrones, drifters), simultaneously acquired ocean and atmosphere data east of the island of Barbados and further south, up to the border of French Giuana. This way, ocean and atmospheric data was acquired in two contrasting regions: (1) the Trade wind region and (2) a region filled with mesoscale eddies. Operations allowed investigating upper ocean processes from small to mesoscale and from sub-diurnal to monthly.A variety of mesoscale eddies were crossed with diverse characteristics, ranging from shallow cyclonic and anticyclonic eddies to the deep reaching structures. Some of these eddies, and in particular North Brazil Rings, have been previously observed and described in dedicated oceanographic experiments. Nonetheless, the EUREC4A-OA/ATOMIC campaign brings in new details about the vertical structure, the dynamics and the potential impact on air-sea interactions of these mesoscale features.With the various observing platforms it was possible to sample the upper-ocean in great detail, resolving frontal scales and stratification. For example, the remnants of the Amazon plume, flowing northward along the shelf-break and being advected far offshore though NBC rings, create a rich variety of submesoscale fronts and a strong barrier layer impacting air-sea exchange of heat and momentum. The ongoing analyses on the ocean dynamics regional and local structures and specifics of air-sea interaction will be highlighted in this presentation

The EUREC4A-Ocean/Atmosphere campaign: status

International audienceThe ocean fine scale (from the mesoscale to the submesoscale) is susceptible to impact air-sea exchange and has an integral effect on the large scale atmosphere and ocean dynamics. Many recent advances in understanding underlying processes have been obtained from modeling efforts and only few in-situ observational studies exist one of them being the EUREC4A-OA/ATOMIC campaign that was added to the EUREC4A atmospheric campaign. This experiment took place in January-February 2020 in the Northwest Tropical Atlantic Ocean with the aim to collect synchronized ocean and atmosphere data to improve our understanding of the role of fine scale processes in the internal ocean dynamics and air-sea interaction.Four oceanographic vessels, coordinated with air-borne observations and autonomous ocean platforms (underwater gliders, Saildrones, drifters), simultaneously acquired ocean and atmosphere data east of the island of Barbados and further south, up to the border of French Giuana. This way, ocean and atmospheric data was acquired in two contrasting regions: (1) the Trade wind region and (2) a region filled with mesoscale eddies. Operations allowed investigating upper ocean processes from small to mesoscale and from sub-diurnal to monthly.A variety of mesoscale eddies were crossed with diverse characteristics, ranging from shallow cyclonic and anticyclonic eddies to the deep reaching structures. Some of these eddies, and in particular North Brazil Rings, have been previously observed and described in dedicated oceanographic experiments. Nonetheless, the EUREC4A-OA/ATOMIC campaign brings in new details about the vertical structure, the dynamics and the potential impact on air-sea interactions of these mesoscale features.With the various observing platforms it was possible to sample the upper-ocean in great detail, resolving frontal scales and stratification. For example, the remnants of the Amazon plume, flowing northward along the shelf-break and being advected far offshore though NBC rings, create a rich variety of submesoscale fronts and a strong barrier layer impacting air-sea exchange of heat and momentum. The ongoing analyses on the ocean dynamics regional and local structures and specifics of air-sea interaction will be highlighted in this presentation

Clonal hematopoiesis driven by chromosome 1q/MDM4 trisomy defines a canonical route toward leukemia in Fanconi anemia

International audienceFanconi anemia (FA) patients experience chromosome instability, yielding hematopoietic stem/progenitor cell (HSPC) exhaustion and predisposition to poor-prognosis myeloid leukemia. Based on a longitudinal cohort of 335 patients, we performed clinical, genomic, and functional studies in 62 patients with clonal evolution. We found a unique pattern of somatic structural variants and mutations that shares features of BRCA-related cancers, the FA-hallmark being unbalanced, microhomology-mediated translocations driving copy-number alterations. Half the patients developed chromosome 1q gain, driving clonal hematopoiesis through MDM4 trisomy downmodulating p53 signaling later followed by secondary acute myeloid lukemia genomic alterations. Functionally, MDM4 triplication conferred greater fitness to murine and human primary FA HSPCs, rescued inflammation-mediated bone marrow failure, and drove clonal dominance in FA mouse models, while targeting MDM4 impaired leukemia cells in vitro and in vivo. Our results identify a linear route toward secondary leukemogenesis whereby early MDM4-driven downregulation of basal p53 activation plays a pivotal role, opening monitoring and therapeutic prospects