CNRS UMR 9019 Paris-Saclay
Intégrité du génome et cancer
Gustave Roussy, Villejuif
contact : Eric JULIEN (Inserm/CNRS)
Replication stress resulting from slowing or stalling of DNA replication forks is a major driver of genome instability during cancer initiation and progression. DNA replication can be challenged as a consequence of oncogene activation or by agents that interfere with DNA synthesis, such as the ones used in chemotherapy. To accomplish genome duplication and prevent chromosomal instability, cells have evolved mechanisms that protect, stabilize and/or restart replication forks while delaying cell cycle progression, which avoids entering mitosis with under-replicated DNA. Over the last years, however, work from several laboratories including ours has shown that cells can progress into mitosis with under-replicated DNA. This led to the identification of mechanisms, mediated by the Fanconi anemia (FA) and Homologous Recombination (HR) repair pathways, that promote post-replication repair and rescue of under-replicated DNA in mitosis, allowing cells to divide and continue proliferating. I will discuss how these findings have advanced our understanding of the link between replication stress and genome instability; I will present a molecular pathway that connects mitochondrial stress and functions of FA proteins in genome maintenance; finally, I will show that mechanisms involved in mitotic rescue of under-replicated DNA may represent promising targets to selectively kill cancer cells that sustain intrinsically high levels of replication stress.
Centre d'Immunologie de Marseille-Luminy (CMIL), CNRS-INSERM, Université Aix-Marseille
contact : Laurent Le Cam (Inserm)
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.
Situé dans le Parc Euromédecine, l'Institut de Recherche en Cancérologie de Montpellier (U1194) est localisé sur le Campus Val d'Aurelle (ICM, Institut régional du Cancer Montpellier / Val d'Aurelle).
Centre de Recherche U1194 soutenu par l'Inserm, l'Université de Montpellier et l'Institut du Cancer de Montpellier (ICM)
Institut de Recherche en Cancérologie de
