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Hugues de Thé
Collège de France
Oncologie cellulaire et moléculaire
Année 2023-2024
Exploring the World of Protein Post-translational Modifications
Conférence - Tony Hunter : New Insights into Intercellular Crosstalk between Different Cell Populations in Pancreatic Tumors That Can Be Translated into the Clinic
Tony Hunter
Salk Institute, La Jolla, California, USA
Résumé
Pancreatic adenocarcinoma (PDA) is one of the most lethal cancers, primarily due to late diagnosis. PDA is a highly stromal (desmoplastic) and poorly vascularized tumor with a dense extracellular matrix; only ~10% of the cells in the tumor are tumor cells, with the rest of the tumor microenvironment (TME) being comprised of cancer-associated fibroblasts (CAFs, and immune cells, including tumor-associated macrophages (TAMs). To investigate the role of cellular crosstalk between CAFs and tumor cells TME, we set out to identify paracrine factors secreted by activated CAFs in the tumor tissue that act on the tumor cells and can be targeted for therapeutic purposes. Through these studies, we identified the LIF (leukemia inhibitory factor) cytokine, secreted by activated CAFs, that acts on tumor cells to promote survival and maintain stemness, thereby serving as a driver of PDA progression. We have shown that therapeutic targeting of LIF by a neutralizing anti-LIF monoclonal antibody in the G12V KRas/Δp53 KPC mouse model of PDA prolongs survival and increases sensitivity to chemotherapy, implicating LIF signaling as a therapeutic resistance mechanism. We found that LIF levels are elevated in human PDA tissue, and that high LIF levels correlate with disease progression. Serum LIF levels are also elevated in PDA patients and correlate with disease stage, suggesting that LIF could be a useful PDA biomarker, as well as a target for combination PDA therapy. Phase 2 PDA clinical trials with a humanized neutralizing anti-LIF mAb in combination with an anti-PD-L1 mAb are underway.
Recently, we have shown that an HDAC inhibitor in combination with gemcitabine slows the growth of KPC tumors by acting on the CAFs to block desmoplastic signals, and also to reduce expression of LIF. We have also found that LIF contributes to PDA tumor cell resistance to T cell killing, and that mAb neutralization of LIF can enhance the PDA tumor cell killing activity of an engineered T cell line. We are currently exploring the role of oncostatin M (OSM), a cytokine related to LIF that is predominantly made by TAMs, in intercellular crosstalk in PDA and tumor progression, to determine if OSM could be another PDA drug target.
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Hugues de Thé
Collège de France - Année 2023-2024
Oncologie cellulaire et moléculaire
Colloque - Explorer la réponse thérapeutique in vivo : Cellular Responses to DNA Damage: From Stalled Forks to Inflammation and Beyond
Intervenant(s)
Philippe Pasero
Institut de Génétique Humaine, CNRS et université de Montpellier
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Hugues de Thé
Collège de France - Année 2023-2024
Oncologie cellulaire et moléculaire
Colloque - Explorer la réponse thérapeutique in vivo : Targeting the DNA Damage Response and Immune Response Interplay: Novel Therapeutic Opportunities
Intervenant(s)
Sophie Postel-Vinay
Institut Gustave Roussy et University College of London
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Hugues de Thé
Collège de France - Année 2023-2024
Oncologie cellulaire et moléculaire
Colloque - Explorer la réponse thérapeutique in vivo : Sources of Endogenous DNA Damage and Mutations in Blood – It's Not Just Water and Oxygen
Intervenant(s)
Ketan Patel
Chief Scientist CRUK Director of the Weatherall Institute of Molecular Medicine Oxford University
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Hugues de Thé
Collège de France
Oncologie cellulaire et moléculaire
Année 2023-2024
Exploring the World of Protein Post-translational Modifications
Conférence - Tony Hunter : Noncanonical Protein Phosphorylation – Is Histidine Phosphorylation Used as a Reversible Regulatory Mechanism?
Tony Hunter
Salk Institute, La Jolla, California, USA
Résumé
Protein phosphorylation is not restricted to serine, threonine and tyrosine, but can occur on six other amino acids, including histidine. In this lecture, I will discuss what is known about non-canonical protein phosphorylation, focusing on our recent work developing new tools to study histidine phosphorylation in cells and tissues, and their use to investigate the possible roles of histidine phosphorylation in liver cancer, pediatric neuroblastoma, breast cancer and pancreatic cancer.
Histidine phosphorylation of proteins was discovered in 1962, before tyrosine phosphorylation, but much less is known about this PTM because phosphohistidine is chemically very labile and therefore hard to study. We set out to investigate histidine phosphorylation over thirty years ago but were stymied by the lack of key reagents. Because anti-phosphotyrosine antibodies have been so useful in studying tyrosine phosphorylation, we set out to develop anti-pHis antibodies, using chemically stable pHis analogues as antigens. We were successful in generating rabbit monoclonal antibodies selective for the 1-pHis and 3-pHis isoforms of phosphohistidine (pHis), using synthetic peptides containing the 1-Tza and 3-pTza pHis analogues as antigens, respectively. We have carried out structural studies of these mAbs bound to their cognate pTza peptide, which reveal how these mAbs achieve isoform specificity, and we have recently used these structures to engineer a higher affinity anti-3-pHis mAb. We have also exploited these mAbs to survey the pHis phosphoproteome, using mass spectrometry to identify novel sites of histidine phosphorylation and new pHis-containing proteins, which we are exploring.
I will go on to describe how we have utilized these mAbs to investigate roles for histidine phosphorylation in cancer, showing that elevated histidine phosphorylation is a potential driver of hepatocellular carcinoma and pediatric neuroblastoma. Finally, I will discuss ongoing work investigating a role for histidine phosphorylation in triple negative breast cancer and pancreatic cancer, and, in particular, a possible role for histidine phosphorylation in the formation and function of invadopodia structures in neuroblastoma cell invasiveness.
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Hugues de Thé
Collège de France
Oncologie cellulaire et moléculaire
Année 2023-2024
Exploring the World of Protein Post-translational Modifications
Conférence - Tony Hunter : Crosstalk between Post-translational Modifications: The Role of Ptm Crosstalk in Protein Degradation
Tony Hunter
Salk Institute, La Jolla, California, USA
Résumé
In this lecture I will discuss the role of PTMs in increasing proteome complexity, why this is important for organisms with genomes of limited protein-coding capacity, and how the combinatorial use of PTMs on a single protein molecule can diversify signal outputs. I will go on to discuss examples of crosstalk between different PTMs in the context of transcriptional regulation mediated by posttranslational modifications of histone tails, and how different PTMs can be used to tag proteins for inducible degradation by the ubiquitin-proteasome system (UPS).
The modification of proteins by ubiquitin and ubiquitin-like proteins, such as SUMO, is second only to phosphorylation in terms of the number of sites modified in the mammalian proteome. I will discuss the versatility of ubiquitylation as a regulatory mechanism, and will review the different classes of ubiquitin ligases, deubiquitylating enzymes and ubiquitin binding domains, and the different members of the ubiquitin-like protein family, such as SUMO.
I will go on to discuss the discovery of RING finger E3 ubiquitin ligases, and, to illustrate their roles in PTM crosstalk, describe our own work on the c-Cbl RING domain protein as a phosphotyrosine-dependent E3 ubiquitin ligase that targets activated receptor tyrosine kinases, and the RNF4 RING domain protein as a SUMO-dependent E3 ubiquitin ligase (STUbL) that is critical in the DNA damage response.
I will end with a description of how we used a budding yeast genetic screen to discover that the RNF4 E3 ligase plays a role in quality control of RNA polymerase III complex assembly, and discuss recent follow up mouse experiments on RNA polymerase III disease mutations that cause a fatal human neurogenerative disease, that could potentially be treated with a sumoylation pathway inhibitor.
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Hugues de Thé
Collège de France
Oncologie cellulaire et moléculaire
Année 2023-2024
Exploring the World of Protein Post-translational Modifications
Conférence - Tony Hunter : Post-translational Modifications of Proteins – Why Nature Chose Phosphate to Modify Proteins
Tony Hunter
Salk Institute, La Jolla, California, USA
Résumé
This lecture will provide an introduction to the world of post-translational modifications (PTMs) of proteins. Chemical modifications of protein surfaces serves as a mechanism to increase proteome diversity. More than 400 different PTMs are known, and PTM linkages can be either reversible or irreversible in nature. PTMs serve many functions, but reversible PTMs play particularly important roles in signal transduction, protein-protein interactions, subcellular localization of proteins and protein degradation. All reversible PTMs, such as phosphorylation, utilize a writer enzyme that adds the PTM and an eraser enzyme that removes the PTM, and in many cases the modified protein is recognized by a reader protein that binds to the PTM itself in a local sequence-dependent manner, serving as a mechanism to read out the PTM signal.
I will review the major types of PTMs and their functions, focusing on protein phosphorylation, which is the most prominent PTM in eukaryotic cells. I will discuss the 150-year history of protein phosphorylation and why phosphorylation was selected as a PTM during evolution, the serendipitous discovery of tyrosine phosphorylation in 1979, and the development of selective tyrosine kinase inhibitors (TKIs) that target aberrant tyrosine phosphorylation. Currently, over 80 TKIs have been approved for use in cancer therapy and treatment of inflammatory conditions.
In the second half of the lecture, I will talk about the discovery of the Pin1 prolyl isomerase, the characterization of Pin1 as a pSer/Thr.Pro motif reader and its activity as a cis-trans prolyl isomerase. By isomerizing pSer/Thr.Pro sites, Pin1 regulates multiple signaling pathways and processes that utilize proline-directed protein kinases, like the CDKs and MAP kinases, including cell cycle progression and mitotic signaling. Cancer-associated proteins, such p53 and Myc, are important targets for Pin1, and I will discuss the reported role of Pin1 in breast cancer and pancreatic cancer, and efforts to generate Pin1-selective small molecule inhibitors for use in cancer therapy. Finally, I will talk about our unpublished work identifying a role for Pin1 in bladder cancer, which implicates Pin1 in regulating cholesterol biosynthesis.
Tony Hunter
Tony Hunter received his BA and PhD from the University of Cambridge, and did postdoctoral studies there and at the Salk Institute. Since 1975, he has been on the faculty of the Salk Institute, where he is the Renato Dulbecco Chair. In 1979, through his work on tumor viruses, he discovered a new class of protein kinases that phosphorylate tyrosine in proteins, establishing that dysregulated tyrosine phosphorylation by an activated tyrosine kinase can cause cancer. Tyrosine phosphorylation is a reversible protein modification essential for the regulation of a wide variety of cellular processes in multicellular eukaryotes, including transmembrane signal transduction by surface receptors. Hunter's work led to the realization that aberrant tyrosine phosphorylation is causal in several types of human cancer, and this has led to the successful development of small molecule inhibitors that target disease-causing tyrosine kinases, known as TKIs, such as GleevecTM.
Hunter has received many awards for his work on tyrosine phosphorylation, including the Sjöberg Prize for Cancer Research, and the Tang Prize for Biopharmaceutical Science, and is a Fellow of the Royal Society of London and a Member of the US National Academy of Sciences.
In recent work, he has been studying histidine phosphorylation of proteins, generating monoclonal antibodies specific for the two isoforms of phosphohistidine, which he is using to identify new histidine phosphorylated proteins, and to uncover a possible role for histidine phosphorylation in cancer. He is also investigating the role of stromal cells in pancreatic cancer, discovering that the leukemia inhibitory factor (LIF) cytokine secreted by cancer-associated fibroblasts is important for tumor progression.
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Hugues de Thé
Collège de France - Année 2023-2024
Oncologie cellulaire et moléculaire
Colloque - Journée François Jacob : La vie sociale des microbes - Microbial Ecosystems – Everything is Everywhere, but the Environment Selects
Intervenant(s)
Nassos Typas, EMBL, Heidelberg, Germany
Les Journées François Jacob
Les Journées François Jacob, organisées par l'Institut de Biologie du Collège de France, rassemblent chaque année les meilleurs spécialistes français et étrangers autour d'un thème à la pointe des enjeux de la recherche en biologie.
Le lauréat du prix Antoine Lacassagne, attribué chaque année par le Collège de France à un chercheur en biologie, est traditionnellement invité à recevoir son prix lors des Journées François Jacob et à y donner un séminaire en relation avec ses travaux.
Ces journées sont nommées en l'honneur de François Jacob, titulaire de la chaire Génétique cellulaire du Collège de France (1964-1991), prix Nobel de physiologie ou médecine 1965 avec André Lwoff et Jacques Monod pour la découverte de la régulation génétique de la synthèse des enzymes et des virus.
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Hugues de Thé
Collège de France - Année 2023-2024
Oncologie cellulaire et moléculaire
Colloque - Journée François Jacob : La vie sociale des microbes - Microbial Interactions in the Vaginal Environment: Revisiting the Normal and the Pathological
Intervenant(s)
Samuel Alizon, Chercheur, Centre interdisciplinaire de recherche en biologie (CIRB - « Écologie et évolution de la santé ») – DR2 CNRS
Les Journées François Jacob
Les Journées François Jacob, organisées par l'Institut de Biologie du Collège de France, rassemblent chaque année les meilleurs spécialistes français et étrangers autour d'un thème à la pointe des enjeux de la recherche en biologie.
Le lauréat du prix Antoine Lacassagne, attribué chaque année par le Collège de France à un chercheur en biologie, est traditionnellement invité à recevoir son prix lors des Journées François Jacob et à y donner un séminaire en relation avec ses travaux.
Ces journées sont nommées en l'honneur de François Jacob, titulaire de la chaire Génétique cellulaire du Collège de France (1964-1991), prix Nobel de physiologie ou médecine 1965 avec André Lwoff et Jacques Monod pour la découverte de la régulation génétique de la synthèse des enzymes et des virus.
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Hugues de Thé
Collège de France - Année 2023-2024
Oncologie cellulaire et moléculaire
Colloque - Journée François Jacob : La vie sociale des microbes - The Ecology and Evolution of E. Coli Virulence
Intervenant(s)
François Blanquart, Chercheur, Centre interdisciplinaire de recherche en biologie (CIRB - «Épidémiologie évolutive des maladies infectieuses») – CRCN, CNRS
Les Journées François Jacob
Les Journées François Jacob, organisées par l'Institut de Biologie du Collège de France, rassemblent chaque année les meilleurs spécialistes français et étrangers autour d'un thème à la pointe des enjeux de la recherche en biologie.
Le lauréat du prix Antoine Lacassagne, attribué chaque année par le Collège de France à un chercheur en biologie, est traditionnellement invité à recevoir son prix lors des Journées François Jacob et à y donner un séminaire en relation avec ses travaux.
Ces journées sont nommées en l'honneur de François Jacob, titulaire de la chaire Génétique cellulaire du Collège de France (1964-1991), prix Nobel de physiologie ou médecine 1965 avec André Lwoff et Jacques Monod pour la découverte de la régulation génétique de la synthèse des enzymes et des virus.
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Hugues de Thé
Collège de France - Année 2023-2024
Oncologie cellulaire et moléculaire
Colloque - Journée François Jacob : La vie sociale des microbes - How Intracellular Life Turns Symbiotic Bacteria into Pathobionts
Intervenant(s)
Olivier Espeli, Chercheur, Centre interdisciplinaire de recherche en biologie (CIRB - « Dynamique des chromosomes ») – DR1 CNRS
Les Journées François Jacob
Les Journées François Jacob, organisées par l'Institut de Biologie du Collège de France, rassemblent chaque année les meilleurs spécialistes français et étrangers autour d'un thème à la pointe des enjeux de la recherche en biologie.
Le lauréat du prix Antoine Lacassagne, attribué chaque année par le Collège de France à un chercheur en biologie, est traditionnellement invité à recevoir son prix lors des Journées François Jacob et à y donner un séminaire en relation avec ses travaux.
Ces journées sont nommées en l'honneur de François Jacob, titulaire de la chaire Génétique cellulaire du Collège de France (1964-1991), prix Nobel de physiologie ou médecine 1965 avec André Lwoff et Jacques Monod pour la découverte de la régulation génétique de la synthèse des enzymes et des virus.
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Hugues de Thé
Collège de France - Année 2023-2024
Oncologie cellulaire et moléculaire
Colloque - Journée François Jacob : La vie sociale des microbes - Physical Properties of Single Cells and Social Behaviour in Dictyostelium Discoideum
Intervenant(s)
Silvia De Monte, CNRS IBENS & Max Planck Institute for Evolutionary Biology, Plön, Germany
Les Journées François Jacob
Les Journées François Jacob, organisées par l'Institut de Biologie du Collège de France, rassemblent chaque année les meilleurs spécialistes français et étrangers autour d'un thème à la pointe des enjeux de la recherche en biologie.
Le lauréat du prix Antoine Lacassagne, attribué chaque année par le Collège de France à un chercheur en biologie, est traditionnellement invité à recevoir son prix lors des Journées François Jacob et à y donner un séminaire en relation avec ses travaux.
Ces journées sont nommées en l'honneur de François Jacob, titulaire de la chaire Génétique cellulaire du Collège de France (1964-1991), prix Nobel de physiologie ou médecine 1965 avec André Lwoff et Jacques Monod pour la découverte de la régulation génétique de la synthèse des enzymes et des virus.
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Hugues de Thé
Collège de France - Année 2023-2024
Oncologie cellulaire et moléculaire
Colloque - Journée François Jacob : La vie sociale des microbes - Mechanics Guide Bacterial Surface Motility and Biofilm Formation
Intervenant(s)
Alexandre Persat, School of Life Sciences, EPFL, Switzerland
Les Journées François Jacob
Les Journées François Jacob, organisées par l'Institut de Biologie du Collège de France, rassemblent chaque année les meilleurs spécialistes français et étrangers autour d'un thème à la pointe des enjeux de la recherche en biologie.
Le lauréat du prix Antoine Lacassagne, attribué chaque année par le Collège de France à un chercheur en biologie, est traditionnellement invité à recevoir son prix lors des Journées François Jacob et à y donner un séminaire en relation avec ses travaux.
Ces journées sont nommées en l'honneur de François Jacob, titulaire de la chaire Génétique cellulaire du Collège de France (1964-1991), prix Nobel de physiologie ou médecine 1965 avec André Lwoff et Jacques Monod pour la découverte de la régulation génétique de la synthèse des enzymes et des virus.
- Visa fler
