I will present two discoveries from my team dealing with precision medicine approaches and possibilities. The first part deals with widely used genotoxic cancer therapy, such as irradiation. These modalities operate through extensive induction of DNA breaks, yet cancer cells frequently display resistance to such interventions. Intriguingly, studies following the dynamics of radiation-induced DNA lesions have identified a temporally distinct and unexplained secondary wave of DNA breaks. Here, I will present our findings on a new pathway that allows tolerance to genotoxic stress. We uncovered that cancer cells actively and reversibly elevate levels of DNA breaks, a mechanism that acts to strengthen the G2/M cell cycle checkpoint thereby limiting premature re-entry into the cell cycle. I will explain the mechanisms underlying this response, which is distinct for cancer cells. Collectively, our findings highlight an unanticipated discovery in cancer biology, demonstrating that tumor cells deploy regulated DNA breaks as a mechanism to delimit the detrimental effects of exogenous DNA double-strand breakage and ensure survival. Finally, in the second part of my presentation I will outline our new approach to determine the phenotypic impact of genetic variants including their impact on drug responses. We call our approach CRISPR-Select, which allows for precise, quantitative, and rapid analysis without the need for generation of clones or selection. It provides unique opportunities for example to identify cancer-causing or drug-response predicting mutations.   

Dr. Cheryl Lyn Walker directs the Center for Precision Environmental Health at Baylor College of Medicine, where she holds the Alkek Presidential Chair in Environmental Health.  Her research focuses on the epigenetic machinery responsible for “reading, writing and erasing” histone modifications, and the newly discovered role for this machinery outside the nucleus, where it acts directly on the cytoskeleton to regulate the function of microtubules and actin filaments.  Several histone methyltransferases, including SETD2 and NSD3 add methyl marks to key lysine residues of microtubules on the mitotic spindle and neuronal cytoskeleton.  Chromatin remodeling proteins that recognize histone PTMs also “read” these methyl marks on microtubules, including PBRM1 of the pBAF SWI/SNF complex.  In the case of methyl marks on the mitotic spindle, both the SETD2 “writer” and the PBRM1 “reader” are required for genomic stability.  In addition to studying how defects in this machinery drive cancer via perturbation of both chromatin and cytoskeletal functions, her group is also elucidating cell signaling pathways and post-translational modifications that alter the activity of these dual-function chromatin and cytoskeleton remodelers.   Dr. Walker is the recipient of an R35 Outstanding Investigator Award from the NCI and is a member of the National Academy of Medicine.

Type I interferons (IFNs) activate intracellular antimicrobial programmes and influence the development of innate and adaptive immune responses. We will discuss our results by addressing the biology of IFN in Down syndrome (DS). This syndrome is the consequence of a chromosomal anomaly known as "trisomy 21" in which chromosome 21 is partially or totally tripled. The subunits that make up the IFN-I receptor (IFNAR1 and IFNAR2), like other genes of immunological relevance, are encoded on this chromosome and their expression is severely increased. This generates an important immunological dysregulation. We will discuss the features of the T cell compartment, Tregs functionality, and the impact of IFN signalling on the different T cell subsets, that could explain the different susceptibilities of this population to develop some pathologies such as solid tumors and autoimmunity. On the other hand, competent type I IFN signalling underlies most anti-tumor immune mechanisms and has recently proven critical to the efficacy of several anticancer agents and immunotherapy.  In this talk, we will discuss our recent findings regarding the potential of TLR agonists as type I-IFN inducers and consequently, as strong modulators of the tumor infiltrate composition, capable of switching the immune suppressive tumor environment to anti-tumor immunity.

Soon to be completed...

A role of a new RAD51/DMC1 remodeler in mammalian recombination

Evénement organisée par Dr Etienne Brain et Dr Elisabeth Lucchi, avec le soutien de la Direction de l’Enseignement, ce séminaire aura lieu le 30 juin 2023, à partir de 09h00, en format présentiel, au sein de l’Institut Curie, site de Saint-Cloud (Salle Bourdin, 35 rue Dailly, 92210)

Paul Gougis from the RT2 group will be conducting a presentation on the topic of chatGPT for scientific writing on Tuesday, June 6th at 14:00.

During the presentation, he will address practical aspects of utilizing chatGPT for medical writing, as well as some broader considerations.

The session will be conducted in English and will be recorded for future reference.

https://www.bdr.riken.jp/en/research/labs/obata-f/index.html

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https://www.ualberta.ca/cellbiology/people/faculty/edan-foley.html

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Le domaine de l'imagerie médicale a connu un essor important au cours des 20 dernières années, avec la démocratisation de l'IRM multiparamétrique tant en préclinique qu'en clinique. Ces évolutions technologiques en matière d'acquisition se sont accompagnées du développement de nouvelles méthodes d'analyse permettant d'extraire des informations quantitatives de ces images. Des approches de radiomique et d'apprentissage profond ont notamment été développées. Au final, de nombreuses études ont montré des corrélations entre certaines métriques et un diagnostic ou une évolution pathologique. Ces métriques sont communément appelées biomarqueurs d'imagerie.
Cette présentation exposera les travaux menés par notre équipe à l'Institut des Neurosciences de Grenoble, sur le développement et la validation de nouveaux biomarqueurs d'imagerie appliqués aux glioblastomes dans différentes études précliniques et cliniques. Nos thèmes de recherche portent sur le développement de nouvelles méthodes d'acquisition IRM et sur le développement de méthodes d'analyse dédiées à l'imagerie médicale basées sur l'apprentissage automatique et l'apprentissage profond. Cette présentation se focalisera sur les glioblastomes, mais nous verrons que ces méthodes peuvent être appliquées à d'autres modalités d'imagerie et à d'autres pathologies cérébrales.

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Séminaire proposé par Pierre LEOPOLD

Animals from cockroaches to baboons in the wild instinctively mix a healthy, balanced diet. Why can’t we? In this lecture I describe my 35-year research journey with colleague David Raubenheimer to discover the answers to this question. Our scientific detective story involves (among other things) a mediaeval woodland in Oxford, biblical African swarms, cannibal Mormons crickets, a new explanation for the human obesity epidemic, the gift of a Picasso painting, and the establishment of a cathedral to multidisciplinary research in Australia. We show that mixing a nutritionally balanced diet relies on a small number of nutrient-specific appetites, which are universal across the animal kingdom. We discover that we too have these appetites, but they have been hijacked in the modern industrialized food environment, causing the epidemics of obesity and the serious diseases that come with it. We need to listen to our appetites and to place them in a whole-food environment where they can guide us towards a healthy balanced diet - without the need for apps or diet fads.

Dr. Artyomov will present  his work in immune aging where his laboratory using characterized immune aging in mouse tissues identifying GZMK+ CD8 T cells as uniform hallmark of aging. In parallel effort profiling of human circulating immune cells revealed existence of dedicated GZMK+ CD8 effector memory T cells in the peripheral blood that accumulate with age. We will discuss their transcriptional regulation and potential biological implications.

During vertebrate development, clustered Hox genes are activated in a precise time-sequence, leading to patterns necessary to properly establish the body plan. The mechanism underlying this in cis timing phenomenon (the Hox timer), which is implemented throughout the neck of the developmental hourglass, has remained elusive ever since its initial observation in 1989, due to the difficulty to approach it using early gastrulating mouse embryos. I will discuss our recent results using pseudo-embryos produced out of ES cells (‘gastruloids’) as an alternative approach to address this question and will show that the temporal dynamic of the system may rely upon the use of series of CTCF sites as successive boundary elements, the directionality of the mechanism being fixed by the asymmetric loading of cohesin complexes. While this mechanism can secure the deployment of Hox gene transcription and hence the proper establishment of axial structures within any given vertebrate species, it also offers some evolutionary flexibility, for minimal modifications in the number, position or affinity of these sites would translate into heterochronic transcription.

The range of vaccines developed against SARS-CoV-2 gave a unique opportunity to study immunization across different platforms. In a single-center cohort with more than 400 volunteers, we analysed the humoral and cellular immune compartments following five COVID-19 vaccines spanning three technologies (adenoviral, mRNA, and inactivated-virus) administered in 16 combinations. Quantification of specific IgG and IgA anti-spike together with the evaluation of the neutralizing activity of the sera, measurement of spike-specific IFNϒ production, and single cell proteomic analysis of spike-binding memory B cells allowed us to determine four clearly distinct immune signatures elicited by the different vaccine combinations. Our data indicate that the immune response is shaped by the type of vaccines applied and by the order in which they are delivered. Our data provide a framework for improving future vaccines strategies against pathogens and cancer.

KEYNOTE SPEAKER

Fatima AL-SHAHROUR - ES

SPEAKERS

Reka ALBERT - US

Ozgun BABUR - US

Valentina BOEVA - CH

Giovanni CIRIELLO - CH

Asmund FLOBAK - NO

Connie R. JIMENEZ - NL

Ina KOCH - DE

Vera PANCALDI - FR

Luca PINELLO - US

Julio SAEZ-RODRIGUEZ - DE

Oznur TASTAN – TR

Denis THIEFFRY - FR

Kim THRANE – SE

Vassily HATZIMANIKATIS - CH

Thomas WALTER - FR

Lodewijk WESSELS – NL

Séminaire proposé par Marine Poupon,
Chargée de communication

The diversity across tumors from different patients and even across cancer cells from the same patient makes the picture very complex. The idea of ‘personalized’ or ‘precision’ medicine has been suggested, aiming to find tailored treatment regimen for each patient according to the individual genetic background and tumor molecular profile. This attempt is achievable thanks to sufficient molecular characterization of cancers accumulated using high-throughput technologies and advanced imaging technologies. However, despite availability of cancer multi-scale data, they are not fully exploited to provide the clue on deregulated mechanisms that would guide better patients stratification and to specific treatment in cancer.

to be completed soon

Mononuclear phagocytes (MNP) consist of Langerhans cells, macrophages and dendritic cells (DC). They can become infected by HIV and transport the virus to its primary target cells (CD4 T cells) in association with their antigen presenting cell function. 

We have revealed that the MNPs within anogenital tissues significantly differ to those in other parts of the body and we have defined three that preferentially transmit HIV; (i) epithelial cDC2, (ii) lamina propria langerin+ cDC2 and CD14+ monocyte derived DCs. We have also shown HIV causes MNP to form clusters with T cells within 2 hours of topical application and that the virus preferentially localises to DCs. Furthermore, DCs traffic HIV to lymphoid follicles which provide a conduit for the virus to enter the submucosa where it preferentially interacts with macrophages. 

These observations significantly advance our understanding of HIV transmission by (i) defining the specific MNPs that capture and transmit HIV (ii) demonstrating that transfer of HIV by MNPs to CD4 T cells occurs within mucosal tissue within 2 hours (rather than lymph nodes) and (iii) that HIV is actively trafficked between mucosal tissue compartments. This is essential information for vaccine design and adds important data regarding early seeding of the viral reservoir.

Les interférons de type I (IFN) activent les programmes antimicrobiens intracellulaires et influencent le développement des réponses immunitaires innées et adaptatives. Nous discuterons de nos résultats en abordant la biologie des IFN dans le syndrome de Down (DS). Ce syndrome est la conséquence d'une anomalie chromosomique appelée " trisomie 21 " dans laquelle le chromosome 21 est partiellement ou totalement triplé. Les sous-unités qui composent le récepteur de l'IFN-I (IFNAR1 et IFNAR2), comme d'autres gènes importants pour l'immunologie, sont codés sur ce chromosome et leur expression est fortement augmentée. Cela génère une importante dysrégulation immunologique. Nous discuterons des caractéristiques du compartiment des cellules T, de la fonctionnalité des Tregs, et de l'impact de la signalisation IFN sur les différents sous-ensembles de cellules T, qui pourraient expliquer les différentes susceptibilités de cette population à développer certaines pathologies telles que les tumeurs solides et l'auto-immunité. D'autre part, la signalisation compétente de l'IFN de type I est à la base de la plupart des mécanismes immunitaires anti-tumoraux et s'est récemment avérée essentielle à l'efficacité de plusieurs agents anticancéreux et de l'immunothérapie.  Dans cet exposé, nous discuterons de nos récentes découvertes concernant le potentiel des agonistes TLR en tant qu'inducteurs de l'IFN de type I et, par conséquent, en tant que modulateurs puissants de la composition de l'infiltrat tumoral, capables de faire basculer l'environnement tumoral immunosuppressif vers une immunité anti-tumorale.