Séminaires & conférences






Thursday, January 21, 13h30



 Atelier confiance dans le travail en équipe

Marie-France MAMZER (Equipe ETRES, CRC)


Thursday, January 28, 13h30



 Impact of DNA damage checkpoint deletion in

Metabolic-Associated Fatty Liver Disease (MAFLD)


Maëva SAROUL (Equipe Desdouets, CRC)


Obesity and diabetes are now considered as pandemic social and economic burdens. The liver is a central organ affected by these conditions resulting in Metabolic-Associated Fatty Liver Disease (MAFLD). The global prevalence of MAFLD is currently estimated to 25% in the general population in western countries. MAFLD encompasses a spectrum of liver conditions ranging from simple hepatic steatosis (NAFL) to the concomitant presence of hepatocellular damage (ballooning), Mallory–Denk body formation, and lobular necro-inflammation which defines Non-Alcoholic SteatoHepatitis (NASH). Recently, thanks to murine MAFLD models, we demonstrated an alteration of fatty hepatocytes division with a specific activation of a “DNA Damage Response” (DDR), mediated by two kinases: ATR and ATM. Our study aims to understand the role(s) of these kinases during the MAFLD development.

We have generated mouse models mutated for ATR and/or ATM specifically in hepatocytes, thanks to the CRISPR/Cas9 technology approach. These different mouse models were fed with choline–deficient high-fat diet (CDHFD) in order to induce MAFLD.

Histological analyses revealed that ATRKO and ATMKO livers present less lobular inflammation, hepatocellular injury leading to a lower NAS score compared to control (CTR) livers. In correlation, we observed in these animals a lower hepatic tumor incidence (17% ATRKO and ATMKO vs 25% MAFLD CRT livers). Interestingly, deletion of the two DDR genes (ATR/ATMDKO) induces a higher hepatic tumor incidence (58%). We next performed metabolomics analysis using LC-MS. We observed that ATR/ATMDKO MAFLD livers do not have significant metabolic adaptations compared to MAFLD CRT livers. By contrast, ATRKO or ATMKO MAFLD livers have an enrichment in glutathione metabolism (betain catabolism), suggesting, in these liver tissues, the establishment of a protective mechanisms related to an antioxidative response. To reinforce these data, bioenergetics profiles (seahorse technology) were analyzed on primary MAFLD hepatocytes cultures. We observed a beneficial impact of ATR/ATM deletion on mitochondrial respiratory capacities, with an improvement of basal, maximal respiration, ATP production and an attenuation of proton leak.

Overall, these results suggest that unexpectedly the deletion of ATR or ATM genes in MAFLD livers reduced NASH development by impacting at least on hepatocytes metabolism.



Thursday, February 11, 13h30



 TD nuclear magnettic resonance to visualize

 water, fat, and lean masses in mice

Luciana MORLA (Equipe Crambert, CRC)


 Invité par Guilhem LIGNON et Angélique GOUGELET

Maintaining water homeostasis is fundamental for cellular function. Many diseases and drugs affect water balance and plasma osmolality. Water homeostasis studies in small animals require the use of invasive or terminal methods that make intracellular and extracellular fluid volume (ICF and ECF) monitoring over time stressful and time consuming. We examined the feasibility of monitoring mice ECF by a non‐invasive method, using time‐domain nuclear magnetic resonance (TD‐NMR). This technique allows differentiating protons in a liquid environment (free fluid) from protons in soft tissues containing a majority of either small molecules (lean) or large molecules (fat). Moreover, this apparatus enables rapid, non‐invasive, and repeated measurements on the same animal. We assessed the feasibility of coupling TD‐NMR analysis to a longitudinal metabolic cage study by monitoring mice daily. We determined the effect of a 24‐hour water deprivation on mice body parameters and detected a sequential and overlapping decrease in free fluid and lean mass during water deprivation. Finally, we studied the effect of mineralocorticoids that are known to induce a transient increase in the ECF but for which no direct measurements have been performed in mice. We show for the first time that mineralocorticoids induce a transient ~20 % increase in free fluid in conscious mice. TD‐NMR is therefore the first method to allow direct measurement of discrete changes in the ECF in conscious small animals. This method allows analysis of kinetic changes to stimuli prior to investigating with terminal methods and will allow further understanding of fluid disorders. We will also discuss changes in fat mass and lean during the day and important aspects to take in account when using this tool.




Thursday, February 19, 13h30



 Role of tunneling Nanotubes (TNTs) in the

progression of neurodegenerative diseases and


Chiara ZURZOLO (Institut Pasteur)


 Invitée par Francine BEHAR-COHEN et Jessica ZUCMAN-ROSSI

Progression of pathology in neurodegenerative diseases is mediated by the productive spreading of prion-like protein aggregates from a “donor cell” that is the source of misfolded aggregates, to an “acceptor cell” in which misfolding is propagated by conversion of the normal protein. Although the proteins involved in the various diseases are unrelated, common pathways appear to be utilized for their intercellular propagation and spreading. I will summarize our recent evidence about the mechanisms involved in the intercellular trafficking of protein aggregates involved in prion, Alzheimer’s and Parkinson’s diseases. In particular on the common roles that Tunneling nanotubes (TNTs) and lysosomes play in the formation and spreading of prion-like assemblies. In addition I will summarize our recent findings on the role of TNTs in Glioblastoma using patient derived stem cells and tumor organoids.



Thursday, February 25, 13h30




Juliette PAILLET (Equipe Guido Kroemer)

 Invitée par Angélique Gougelet et Guilhem Lignon ??


Thursday, March 4, 13h30



 Vasopressin and cardiometabolic disease : is

watera new prevention strategy ?

Olle MELANDER (Lund University, Sweden)

Invité par Jessica Zucman-Rossi et Gilles Crambert


Vasopressin (VP), commonly proxie-measured with a stable C-terminal fragment of the precursor hormone called copeptin, is elevated not only in cases of acute diseases with severe water losses (e.g gastroenteritis) or hypotension (e.g septic shock) but also in normal states when water intake is low. This preserves normal plasma osmolality thanks to renal water conservation through VP stimulation of the V2 receptor. However, as will be demonstrated in this talk, high levels of copeptin in the population is linked to markedly increased risk of type 2 diabètes melitus, cardiovascular disease and chronic kidney disease independently of other risk factors. Moreover, obese individuals with high copeptin are at increased risk of non-alcoholic fatty liver disease (NAFLD). A challenging question based on the hypothesis that high VP (measuring by copeptin) is causally related to these diseases, is whether the elevation of cardiometabolic risk in normal subjects with high VP and other signs of low water intake (low urine volume and high urine osmolality) can be reversed by water supplementation. Data from animals and humans to support this hypothesis will be presented.


Thursday, March 11, 13h30




Catherine BLANC et Aurélien CORNEAU,

(CyPS, Pitié-Salpêtrière, Paris)

 Invités par Chiara MAIURI


Thursday, March 18, 13h30



 Dynamics of immune cell coopérations underlying

tumor régressions : lessons from mouse models

Nadège BERCOVICI (Institut Cochin, Paris)


 Invitée par Jonathan POL


Thursday, March 25, 13h30



 Quantifyng the evolutionary dynamics

of human cancers

Trevor GRAHAM (Barts Institute, QMUL London)

Invité par Jessica Zucman-Rossi et Angélique Gougelet



The fundamental evolutionary parameters that define cancer evolution, such as the mutation rate per cell division and selective advantage conferred by each mutation, remain poorly characterised. Here I will discuss how these parameters can be derived from routinely-available cancer genome sequencing data, via statistical inference of mathematical population genetics models of clonal evolution. We measure that positively selected mutations can cause fitness increases as large as 50%, and also explore the dynamics of negatively-selected mutations (neoantigens) in a growing tumour. These quantitative measurements of cancer evolution enable mechanistic forecasting of the future evolution of a tumour.



Thursday, April 22, 13h30



 Novel precision mouse models of liver cancer

Amaia LUJAMBIO (Icahn school of médicine

at mount sinai)

Invitée par Jessica Zucman-Rossi, Chantal Desdouets, Angélique Gougelet



Hepatocellular carcinoma (HCC) represents a major health problem, causing more than 700,000 deaths annually. Although HCC treatment has greatly improved over the last decades, HCC patients diagnosed at advanced stages are ineligible for curative ablative therapies such as liver resection or transplantation. Several multikinase inhibitors, such as sorafenib, regorafenib, and lenvatinib, are approved for the treatment of advanced HCC patients but provide limited survival benefits. Recently, nivolumab and pembrolizumab, two PD1 (programmed cell death 1) immune checkpoint inhibitors, were approved for second line HCC treatment after showing unprecedented results in phase II clinical trials. However, not all patients are sensitive. It is therefore clear that there is an urgent need to identify novel therapies that are more effective and biomarkers for optimal patient selection.To this end, we have created a series of novel mouse models of HCC, each model recapitulating genetic alterations that are frequent in HCC patients. The model is based on the hydrodynamic tail vein delivery of genetic elements to overexpress oncogenes (with transposon-based vectors) and delete tumor suppressor genes (with CRISPR-based vectors). We have established cell lines from each model (13 in total) and are now performing drug and CRISPR screens to identify novel drug targets that are specific for each model. In addition, we have modified the hydrodynamic strategy to interrogate how genetic alterations relevant to human disease affect immune surveillance and response to immunotherapies. In this case, we modulate the immunogenicity of the liver tumors by also expressing model antigens. With this model, we have shown that beta-catenin activation is a novel mechanism of immune escape and immune resistance in HCC. We are currently using this platform to identify additional mechanisms of immune escape in HCC and define novel biomarkers for patient selection..



Thursday, May 20, 13h30



 Titre en attente

Federico MINGOZZI (Sparks Therapeutics)

Invité par Jessica Zucman-Rossi et Sébastien Lacroix-Desmazes




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