Matthieu Najm

Ndèye Maguette Mbaye

Mélanie Lubrano

Tristan Lazard

Thomas Defard

Matthieu Cornet

Inferring diploid 3D chromatin structures from Hi-C data

Jointly embedding multiple single-cell omics measurements

Experimentally-Generated Ground Truth for Detecting Cell Types in an Image-Based Immunotherapy

Evaluation of deep and shallow learning methods in chemogenomics for the prediction of drugs

Urinary Exosomes of Patients with Cystic Fibrosis Unravel CFTR-Related Renal Disease.

The prevalence of chronic kidney disease is increased in patients with cystic fibrosis (CF). The study of urinary exosomal proteins might provide insight into the pathophysiology of CF kidney disease. Urine samples were collected from 19 CF patients (among those 7 were treated by cystic fibrosis transmembrane conductance regulator (CFTR) modulators), and 8 healthy subjects. Urine exosomal protein content was determined by high resolution mass spectrometry. A heatmap of the differentially expressed proteins in urinary exosomes showed a clear separation between control and CF patients. Seventeen proteins were upregulated in CF patients (including epidermal growth factor receptor (EGFR); proteasome subunit beta type-6, transglutaminases, caspase 14) and 118 were downregulated (including glutathione S-transferases, superoxide dismutase, klotho, endosomal sorting complex required for transport, and matrisome proteins). Gene set enrichment analysis revealed 20 gene sets upregulated and 74 downregulated. Treatment with CFTR modulators yielded no significant modification of the proteomic content. These results highlight that CF kidney cells adapt to the CFTR defect by upregulating proteasome activity and that autophagy and endosomal targeting are impaired. Increased expression of EGFR and decreased expression of klotho and matrisome might play a central role in this CF kidney signature by inducing oxidation, inflammation, accelerated senescence, and abnormal tissue repair. Our study unravels novel insights into consequences of CFTR dysfunction in the urinary tract, some of which may have clinical and therapeutic implications.

A Dual Protein-mRNA Localization Screen Reveals Compartmentalized Translation and Widespread

Local translation allows spatial control of gene expression. Here, we performed a dual protein-mRNA localization screen, using smFISH on 523 human cell lines expressing GFP-tagged genes. 32 mRNAs displayed specific cytoplasmic localizations with local translation at unexpected locations, including cytoplasmic protrusions, cell edges, endosomes, Golgi, the nuclear envelope, and centrosomes, the latter being cell-cycle-dependent. Automated classification of mRNA localization patterns revealed a high degree of intercellular heterogeneity. Surprisingly, mRNA localization frequently required ongoing translation, indicating widespread co-translational RNA targeting. Interestingly, while P-body accumulation was frequent (15 mRNAs), four mRNAs accumulated in foci that were distinct structures. These foci lacked the mature protein, but nascent polypeptide imaging showed that they were specialized translation factories. For β-catenin, foci formation was regulated by Wnt, relied on APC-dependent polysome aggregation, and led to nascent protein degradation. Thus, translation factories uniquely regulate nascent protein metabolism and create a fine granular compartmentalization of translation.

Assessing reliability of intra-tumor heterogeneity estimates from single sample whole exome

Tumors are made of evolving and heterogeneous populations of cells which arise from successive appearance and expansion of subclonal populations, following acquisition of mutations conferring them a selective advantage. Those subclonal populations can be sensitive or resistant to different treatments, and provide information about tumor aetiology and future evolution. Hence, it is important to be able to assess the level of heterogeneity of tumors with high reliability for clinical applications. In the past few years, a large number of methods have been proposed to estimate intra-tumor heterogeneity from whole exome sequencing (WES) data, but the accuracy and robustness of these methods on real data remains elusive. Here we systematically apply and compare 6 computational methods to estimate tumor heterogeneity on 1,697 WES samples from the cancer genome atlas (TCGA) covering 3 cancer types (breast invasive carcinoma, bladder urothelial carcinoma, and head and neck squamous cell carcinoma), and two distinct input mutation sets. We observe significant differences between the estimates produced by different methods, and identify several likely confounding factors in heterogeneity assessment for the different methods. We further show that the prognostic value of tumor heterogeneity for survival prediction is limited in those datasets, and find no evidence that it improves over prognosis based on other clinical variables. In conclusion, heterogeneity inference from WES data on a single sample, and its use in cancer prognosis, should be considered with caution. Other approaches to assess intra-tumoral heterogeneity such as those based on multiple samples may be preferable for clinical applications.

Continuous Embeddings of DNA Sequencing Reads and Application to Metagenomics.

Yasmina Djeghmoum

JUNIOR GROUP LEADER POSITION

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Institut Curie (https://institut-curie.org) consists of a hospital and a world-class multidisciplinary research center combining research in cell biology, genetics, epigenetics, immunology, soft matter physics, organic and medicinal chemistry. It includes over 3,300 researchers, physicians, clinicians, technicians and administrative staff working on three sites: Paris, Orsay and Saint-Cloud. The institute facilities include an advanced imaging platform with a wide variety of top-of-the-line microscopes from confocal imaging to super-resolution, for live cell and small animal imaging. Other facilities include single cell technologies, small molecule and CRISPR screening, high throughput sequencing, bioinformatics, proteomics and mass spectrometry, antibody technologies and protein purification, nano-SIMS, cytometry, and animal housing (https://science.institut-curie.org/platforms). In addition, the hospital proximity allows access to large clinical databases and sample collections.

Institut Curie is supporting the recruitment of a junior group leader position, based at its research campus in central Paris in the “Cancer, Heterogeneity, Instability and Plasticity” unit https://science.institut-curie.org/research/integrated-biology/cancer-heterogeneity-instability-and-plasticity-chip/. The six research groups of the unit investigate basic mechanisms of cancer initiation, progression and/or resistance to treatment with particular focus on genetic and epigenetic alterations, tumor microenvironment, DNA repair and computational biology. Applications addressing molecular mechanisms of development of pediatric cancers, dynamics of cancer evolution and innovative therapeutics are welcomed.

We invite applications from outstanding candidates wishing to address questions on fundamental mechanisms of cancer development (“hallmarks of cancer”) using relevant model systems and/or investigating molecular bases of human malignancies. Important criteria for the selection of the candidates will be the outstanding quality of their scientific record and project, as well as their capacity to interface with biologists and clinicians in the department and beyond, and to drive developments in the field of biomedical research on cancer, the main mission of Institut Curie.

The newly recruited group will benefit from state-of-the-art research equipment. Appropriate laboratory space for 6-7 people and a start-up package will also be available. The successful candidate should meet the criteria to compete for national and international funding, and for French institutional research positions (University or INSERM).


Send full CV, motivation letter, 3-4 pages research plan and three reference letters to

For information please contact:

Olivier Delattre: , +33 156246679

Deadline for applications: February 15, 2021. Interviews scheduled in April 2021


Institut Curie is an inclusive, equal opportunities employer and is dedicated to the highest standards of research integrity.

logoHR

JUNIOR GROUP LEADER POSITION

logo1logo2

 

 

 

Institut Curie (https://institut-curie.org) consists of a hospital and a world-class multidisciplinary research center combining research in cell biology, genetics, epigenetics, immunology, soft matter physics, organic and medicinal chemistry. It includes over 3,300 researchers, physicians, clinicians, technicians and administrative staff working on three sites: Paris, Orsay and Saint-Cloud. The institute facilities include an advanced imaging platform with a wide variety of top-of-the-line microscopes from confocal imaging to super-resolution, for live cell and small animal imaging. Other facilities include single cell technologies, small molecule and CRISPR screening, high throughput sequencing, bioinformatics, proteomics and mass spectrometry, antibody technologies and protein purification, nano-SIMS, cytometry, and animal housing (https://science.institut-curie.org/platforms). In addition, the hospital proximity allows access to large clinical databases and sample collections.

Institut Curie is supporting the recruitment of a junior group leader position, based at its research campus in central Paris in the “Cancer, Heterogeneity, Instability and Plasticity” unit https://science.institut-curie.org/research/integrated-biology/cancer-heterogeneity-instability-and-plasticity-chip/. The six research groups of the unit investigate basic mechanisms of cancer initiation, progression and/or resistance to treatment with particular focus on genetic and epigenetic alterations, tumor microenvironment, DNA repair and computational biology. Applications addressing molecular mechanisms of development of pediatric cancers, dynamics of cancer evolution and innovative therapeutics are welcomed.

We invite applications from outstanding candidates wishing to address questions on fundamental mechanisms of cancer development (“hallmarks of cancer”) using relevant model systems and/or investigating molecular bases of human malignancies. Important criteria for the selection of the candidates will be the outstanding quality of their scientific record and project, as well as their capacity to interface with biologists and clinicians in the department and beyond, and to drive developments in the field of biomedical research on cancer, the main mission of Institut Curie.

The newly recruited group will benefit from state-of-the-art research equipment. Appropriate laboratory space for 6-7 people and a start-up package will also be available. The successful candidate should meet the criteria to compete for national and international funding, and for French institutional research positions (University or INSERM).


Send full CV, motivation letter, 3-4 pages research plan and three reference letters to

For information please contact:

Olivier Delattre: , +33 156246679

Deadline for applications: February 15, 2021. Interviews scheduled in April 2021


Institut Curie is an inclusive, equal opportunities employer and is dedicated to the highest standards of research integrity.

logoHR

Emma Torun

Motility and morphodynamics of confined cells.

We introduce a minimal hydrodynamic model of polarization, migration, and deformation of a biological cell confined between two parallel surfaces. In our model, the cell is driven out of equilibrium by an active cytsokeleton force that acts on the membrane. The cell cytoplasm, described as a viscous droplet in the Darcy flow regime, contains a diffusive solute that actively transduces the applied cytoskeleton force. While fairly simple and analytically tractable, this quasi-two-dimensional model predicts a range of compelling dynamic behaviours. A linear stability analysis of the system reveals that solute activity first destabilizes a global polarization-translation mode, prompting cell motility through spontaneous symmetry breaking. At higher activity, the system crosses a series of Hopf bifurcations leading to coupled oscillations of droplet shape and solute concentration profiles. At the nonlinear level, we find traveling-wave solutions associated with unique polarized shapes that resemble experimental observations. Altogether, this model offers an analytical paradigm of active deformable systems in which viscous hydrodynamics are coupled to diffusive force transducers.

Fast recovery of disrupted tip links induced by mechanical displacement of hair bundles.

Hearing and balance rely on the capacity of mechanically sensitive hair bundles to transduce vibrations into electrical signals that are forwarded to the brain. Hair bundles possess tip links that interconnect the mechanosensitive stereocilia and convey force to the transduction channels. A dimer of dimers, each of these links comprises two molecules of protocadherin 15 (PCDH15) joined to two of cadherin 23 (CDH23). The « handshake » that conjoins the four molecules can be disrupted in vivo by intense stimulation and in vitro by exposure to Ca chelators. Using hair bundles from the rat’s cochlea and the bullfrog’s sacculus, we observed that extensive recovery of mechanoelectrical transduction, hair bundle stiffness, and spontaneous bundle oscillation can occur within seconds after Ca chelation, especially if hair bundles are deflected toward their short edges. Investigating the phenomenon in a two-compartment ionic environment that mimics natural conditions, we combined iontophoretic application of a Ca chelator to selectively disrupt the tip links of individual frog hair bundles with displacement clamping to control hair bundle motion and measure forces. Our observations suggest that, after the normal Ca concentration has been restored, mechanical stimulation facilitates the reconstitution of functional tip links.