Centro de Investigación del Cáncer (CIC) and Instituto de Biología Molecular y Celular del Cáncer (IBMCC), CSIC-USAL, Salamanca, Spain
contact : Antonio Maraver (Inserm) -ATTENTION Séminaire décalé au vendredi 02 Juin à 14h
KRAS oncogenes have been identified in a quarter of all human lung tumors. Recently, several inhibitors were developed that target specific mutant KRAS isoforms and two of them, directed against the KRAS G12C oncoprotein, have just been approved. However, most patients develop resistance against these inhibitors and no actual survival benefits have been observed in clinical trials. Thus, it is urgently required to identify novel therapeutic options applicable to most if not all patients with KRAS-mutant tumors. I will discuss what we have learned from genetically engineered mouse models about the development of resistance to KRAS inhibition. Moreover, I will present novel insights into the mechanisms of KRAS signaling in lung cancer and how a better understanding of KRAS signaling may help to overcome resistance to targeting either KRAS itself or its MAPK effector pathway.
Centre de Recherche des Cordeliers, INSERM UMRS1138, Paris
contact : Florence Cammas (Inserm/CNRS)
Vizgen, MEng, MBA, Regional Account Manager
contact : Laurent Le Cam (Inserm)
Biological systems are composed of numerous cell types, intricately organized to form functional tissues and organs. While recent advancements in genomics technologies have made it possible to characterize cell types through careful analysis of the transcriptome, they are unable to resolve how gene expression and cell types are spatially arranged. In this presentation, we introduce you to Vizgen’s all-in-one in situ genomics platform MERSCOPE, which enables the direct profiling of the spatial organization of intact tissue with genomic scale
throughput. The instrument, the MERFISH chemistry and use cases will be presented as well.
Institut Gustave Roussy (IGR)-Paris
contact Julie Constanzo (ICM)
Florent Ginhoux is graduated in Biochemistry from the University Pierre et Marie CURIE (UPMC), Paris VI, obtained a Masters degree in Immunology from the Pasteur Institute in 2000 and his PhD in 2004 from UPMC, Paris VI. As a postdoctoral fellow, he joined the Laboratory of Miriam Merad in the Mount Sinai School of Medicine (MSSM), New York, where he studied the ontogeny and the homeostasis of cutaneous dendritic cell populations, with a strong focus on Langerhans cells and Microglia. In 2008, he became an Assistant Professor in the Department of Gene and Cell Medicine, MSSM and member of the Immunology Institute of MSSM. He joined the Singapore Immunology Network (SIgN), A*STAR in May 2009 as a Junior Principal Investigator and became Senior Principal Investigator in 2014. He joined the EMBO Young Investigator (YIP) program in 2013 and is a Web of Science Highly Cited Researcher since 2016. He is also an Adjunct Visiting Associate Professor in the Shanghai Immunology Institute, Jiao Tong University, in Shanghai, China since 2015 and Adjunct Associate Professor in the Translational Immunology Institute, SingHealth and Duke NUS, Singapore since 2016. He is now a Laboratory Director in Gustave Roussy focusing on pediatric cancers and the role of myeloid cells in tumor progression and became an EMBO member in 2022.
Preclinical and Experimental Research in Thoracic Tumors (PreTT)
IDIBELL - Barcelone
contact : Laurent Le Cam
Genetic and Epigenetic control of normal and malignant hematopoiesis
Institut de Recherche Saint Louis / INSERM U944 / CNRS UMR7212
contact : Antonio Maraver (IRCM-Inserm)
Acute myeloid leukemia (AML) is a type of cancer that affects the blood and bone marrow. It is characterized by the overproduction of immature white blood cells, called myeloblasts, which can crowd out healthy blood cells and lead to a variety of symptoms, including fatigue, infection, and bleeding. AML is the most common acute leukemia diagnosed in adult and has a high relapse rate with a dismal overall 5-year survival of 24%. AML is a complex disease that is driven by a variety of genetic and epigenetic changes but its exact causes are still not fully understood.
Enhancers are non-coding regions of DNA that play a crucial role in regulating gene expression. They act as binding sites for transcription factors to promote gene transcription. Super-enhancers are clusters of enhancers that are characterized by a high density of transcription factor binding sites. They have been characterized as a particular class of enhancers controlling cell type specific gene expression programs and tend to be enriched around and control oncogenes. In leukemia, enhancers have been shown to be key players in the development and progression of the disease. Identification of the direct functional and physical relationship between Super-Enhancers and their target oncogenes could help decipher complex coordinated gene expression programs that lead to leukemogenesis. Study of the dynamic interplay between enhancers, and gene expression program could unravel novel collaborative oncogenic mechanisms and help design more effective combinatorial therapies.
In a recent study we hypothesized that important regulatory regions such as Super-Enhancers could control simultaneously expression of genes cooperating in functional modules to promote leukemia development. To identify key Super-Enhancers that are involved in AML cell growth and survival, we used a screening methodology called CRISPRi, which relies on the use of a deactivated Cas9 protein fused to a KRAB domain to target and inactivate Super-Enhancers. We deployed this strategy in the ETO2-GLIS2 fusion driven model of acute megakaryoblastic leukemia (AMKL), an aggressive pediatric myeloid leukemia with poor prognosis, which mainly relies on the ETO2-GLIS2 as the transforming lesion. Among the top hits of our screen, we identified a novel Super-Enhancer, located 5’ to the KIT gene on chromosome 4. We found that it directly interacts and regulates the expression of KIT and PDGFRA genes, which are both required for leukemia progression in vitro and in vivo. These results suggest that Super-Enhancers could control simultaneously the expression of genes cooperating in functional modules to promote leukemia development.
Our findings provide new insights into the molecular mechanisms underlying AML pathogenesis and highlight the importance of understanding the role of enhancers and Super-Enhancers in the development and progression of leukemias. We believe that systematic screening of essential Super-Enhancers can reveal coordinated regulation of genes involved in cancer cell transformation and cancer progression and could help to uncover novel therapeutic approaches.
Cancer Research Centre of Toulouse (CRCT)/Inserm/Université Paul Sabatier/CNRS
contact : Eric Julien (CNRS/Inserm)
En réponse aux thérapies anti-cancéreuses, des voies de signalisations peuvent être activées et induire une résistance des cellules cancéreuses à ces traitements. Ces voies sont généralement régulées par des oncoprotéines et des interactions protéine-protéine. Notre projet consiste à déterminer les mécanismes moléculaires contrôlant la résistance des tumeurs pancréatiques, en identifiant et inhibant des (onco)protéines et/ou des interactions protéine-protéine cibles. Pour cela, nous développons des méthodes et outils innovants basés sur la technologie des anticorps intracellulaires. Ces anticorps dérivent du domaine variable d’immunoglobulines à simple chaine lourde de camélidés et sont appelés « nanobody ». Ils se lient de façon spécifique à leur cible et peuvent ainsi bloquer leur(s) fonction(s) dans les cellules. Il est également possible de fonctionnaliser ces anticorps avec des molécules effectrices. Par exemple, les anticorps dégradeurs sont fusionnés à une E3 ubiquitine ligase pour induire la dégradation spécifique de leur cible. En utilisant ces technologies, nous inhibons à façon des médiateurs de voies de signalisation afin de définir l’implication de ces dernières dans la résistance des cellules cancéreuses pancréatiques
PredictCan Biotechnologies SAS, Biopôle Euromédecine, Grabels, France.
Contact : Céline Gongora (inserm)
"The company develops (1) innovative tools for early detection of solid tumors, and (2) cutting-edge human-derived 3D models to support drug development and precision medicine.
It is well known that Drug-induced liver injury (DILI) is a major challenge in drug development and most of the compounds that passed preclinical testing fail clinical trials because of liver toxicity. One reason of this failure is that existing preclinical models are unable to reproduce the interindividual heterogeneity of drug response in a population. PredictCan Biotechnologies SAS releases GenuineSelect-TOX, a new donor-dependent reprogramming multicellular spheroid model that recapitulates interindividual heterogeneity found in a cohort of people. Hepatic toxicity analysis revealed that the model could accurately predict clinical DILI confirmed by the FDA (FDA DILIrank). Moreover, the model could also predict chemical-induced hepatotoxicity based on host-risk factors such as age and sex. GenuineSelect-TOX is the first preclinical model that offers the possibility to (1) perform Clinical Trials-in-a-Dish for DILI, and (2) challenge DILI based on host-risk factors. At PredictCan Biotechnologies SAS, we offer an innovative solution to generate on-demand cohorts of healthy individuals for fit-on-purpose analysis of hepatotoxicity of your molecules."