Équipe
Jean-EMMANUEL SARRY
METAML :
Métabolisme et résistance thérapeutique
dans les leucémies aiguës myéloïdes
Le laboratoire d’Excellence Toulouse Cancer est un projet qui vise à comprendre les mécanismes de résistance et de rechute dans les cancers.
Les spécificités
de notre axe de recherche
Les Leucémies Aiguës Myéloïdes (LAM) constituent un ensemble hétérogène d’hémopathies malignes résultant de la transformation de progéniteurs hématopoïétiques. La résistance thérapeutique est la raison majeure des récidives chez les patients atteints de LAM et représente la principale conséquence de leur pronostic défavorable. L’équipe METAML a montré que cette résistance était initiée par des cellules dont les mitochondries ont une activité énergétique et oxydative (« OxPHOS ») très forte après une chimiothérapie conventionnelle mais aussi après de nouvelles thérapies ciblées récemment mise sur le marché. Nous avons également démontré que cette forte activité mitochondriale est due à une adaptation métabolique mise en place par les cellules de LAM en réponse aux stress mitochondriaux induits par les traitements. Ceci conduit à une augmentation des capacités cataboliques, énergétiques et de détoxification des espèces réactives de l’oxygène (ROS), à une grande flexibilité à utiliser différents nutriments et à une plus grande dépendance aux NADH déshydrogénases mitochondriales (en particulier la NADH déshydrogénase du complexe I de la chaîne respiratoire). Nos études ont abouti au dépôt de plusieurs brevets sur de nouvelles cibles moléculaires (e.g. CD39, CALCRL, ADM) dont l’inhibition permet de sensibiliser les cellules résistantes aux chimiothérapies. Plus récemment, nos travaux de recherche nous ont aussi conduit à étudier le rôle du dialogue métabolique au sein de la tumeur et de l’hôte (JE. Sarry), de la régulation transcriptionnelle et de l’épissage de l’ARN (M. Ghisi), ainsi que celui de l’autophagie leucémique et de l’hôte (C. Joffre) dans les mécanismes adaptatifs et métaboliques de la résistance thérapeutique. Tous ces travaux se font dans un contexte fortement à la fois préclinique (modèles murins et de xénogreffe avec le CREFRE) et clinique chez les patients atteints de LAM (S. Bertoli, V. DeMas, O. Rauzy, C. Récher, F. Vergez).
Leucémies aiguës myéloïdes
Métabolisme
Résistance thérapeutique
Stress oxydant
Adaptation métabolique
Adaptation métabolique
Régulation transcriptionnelle et post-transcriptionnelle
Autophagie
Microenvironnement leucémique
Signalisation
Hétérogénéité tumorale
DES PROJETS
DE RECHERCHE
Rôle du dialogue métabolique et du métabolisme systémique dans l’adaptation mitochondrial et la résistance thérapeutique des cellules de LAM.
Jean-Emmanuel Sarry & Fanny Grannat
Régulateurs transcriptionnels et post-transcriptionnels du métabolisme et réponse à la thérapies des LAM
Margherita Ghisi
L’autophagie leucémique et de l’hôte, un acteur majeur dans la résistance thérapeutique des cellules de LAM.
Carine Joffre & Laura Poillet
LES FOCUS
DE L’ÉQUIPE
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PRODUCTIONS SCIENTIFIQUES
PUBLICATIONS 2023
PUBLICATIONS 2022
Dumas, Pierre-Yves, Sarah Bertoli, Caroline Bonmati, Martin Carre, Juliette Lambert, Mario Ojeda-Uribe, Sylvain Chantepie, et al. “Characteristics and Clinical Outcomes of SARS-CoV-2 Infection in Adult Patients with Acute Leukemia in France.” Leukemia Research 120 (June 20, 2022): 106901. https://doi.org/10.1016/j.leukres.2022.106901.
Seiler, Kristina, Magali Humbert, Petra Minder, Iris Mashimo, Anna M. Schläfli, Deborah Krauer, Elena A. Federzoni, et al. “Hexokinase 3 Enhances Myeloid Cell Survival via Non-Glycolytic Functions.” Cell Death & Disease 13, no. 5 (May 11, 2022): 448. https://doi.org/10.1038/s41419-022-04891-w.
Decroocq, Justine, Rudy Birsen, Camille Montersino, Prasad Chaskar, Jordi Mano, Laury Poulain, Chloe Friedrich, et al. “RAS Activation Induces Synthetic Lethality of MEK Inhibition with Mitochondrial Oxidative Metabolism in Acute Myeloid Leukemia.” Leukemia 36, no. 5 (May 2022): 1237–52. https://doi.org/10.1038/s41375-022-01541-0.
Paolillo, Rosa, Mathias Boulanger, Pierre Gâtel, Ludovic Gabellier, Marion De Toledo, Denis Tempé, Rawan Hallal, et al. “The NADPH Oxidase NOX2 Is a Marker of Adverse Prognosis Involved in Chemoresistance of Acute Myeloid Leukemias.” Haematologica, February 17, 2022. https://doi.org/10.3324/haematol.2021.279889.
Birsen, Rudy, Clement Larrue, Justine Decroocq, Natacha Johnson, Nathan Guiraud, Mathilde Gotanegre, Lilia Cantero-Aguilar, et al. “APR-246 Induces Early Cell Death by Ferroptosis in Acute Myeloid Leukemia.” Haematologica 107, no. 2 (February 1, 2022): 403–16. https://doi.org/10.3324/haematol.2020.259531.
Grenier, Adrien, Laury Poulain, Johanna Mondesir, Arnaud Jacquel, Claudie Bosc, Lucille Stuani, Sarah Mouche, et al. “AMPK-PERK Axis Represses Oxidative Metabolism and Enhances Apoptotic Priming of Mitochondria in Acute Myeloid Leukemia.” Cell Reports 38, no. 1 (January 4, 2022): 110197. https://doi.org/10.1016/j.celrep.2021.110197.
PUBLICATIONS 2021
Abdel Hadi, Nadine, Emeline Boet, Airelle Lahalle, Laura Lauture, Alice Refeyton, Gabriela Reyes-Castellanos, Nathalie Caplet, et al. “Meeting Report of the 4th Biennial Metabolism and Cancer Symposium.” The FEBS Journal, November 24, 2021. https://doi.org/10.1111/febs.16295.
Sabatier, Marie, Emeline Boet, Sonia Zaghdoudi, Nathan Guiraud, Alexis Hucteau, Nathaniel Polley, Guillaume Cognet, et al. “Activation of Vitamin D Receptor Pathway Enhances Differentiating Capacity in Acute Myeloid Leukemia with Isocitrate Dehydrogenase Mutations.” Cancers 13, no. 20 (October 19, 2021): 5243. https://doi.org/10.3390/cancers13205243.
Poillet-Perez, Laura, Jean-Emmanuel Sarry, and Carine Joffre. “Autophagy Is a Major Metabolic Regulator Involved in Cancer Therapy Resistance.” Cell Reports 36, no. 7 (August 17, 2021): 109528. https://doi.org/10.1016/j.celrep.2021.109528.
Luna-Yolba, Raquel, Justine Marmoiton, Véronique Gigo, Xavier Marechal, Emeline Boet, Ambrine Sahal, Nathalie Alet, et al. “Disrupting Mitochondrial Electron Transfer Chain Complex I Decreases Immune Checkpoints in Murine and Human Acute Myeloid Leukemic Cells.” Cancers 13, no. 14 (July 13, 2021): 3499. https://doi.org/10.3390/cancers13143499.
Morfoisse, Florent, Fabienne De Toni, Jeremy Nigri, Mohsen Hosseini, Audrey Zamora, Florence Tatin, Françoise Pujol, et al. “Coordinating Effect of VEGFC and Oleic Acid Participates to Tumor Lymphangiogenesis.” Cancers 13, no. 12 (June 8, 2021): 2851. https://doi.org/10.3390/cancers13122851.
Stuani, Lucille, Marie Sabatier, Estelle Saland, Guillaume Cognet, Nathalie Poupin, Claudie Bosc, Florence A. Castelli, et al. “Mitochondrial Metabolism Supports Resistance to IDH Mutant Inhibitors in Acute Myeloid Leukemia.” The Journal of Experimental Medicine 218, no. 5 (May 3, 2021). https://doi.org/10.1084/jem.20200924.
Cartel, Maëlle, Pierre-Luc Mouchel, Mathilde Gotanègre, Laure David, Sarah Bertoli, Véronique Mansat-De Mas, Arnaud Besson, Jean-Emmanuel Sarry, Stéphane Manenti, and Christine Didier. “Inhibition of Ubiquitin-Specific Protease 7 Sensitizes Acute Myeloid Leukemia to Chemotherapy.” Leukemia 35, no. 2 (February 2021): 417–32. https://doi.org/10.1038/s41375-020-0878-x.
Larrue, Clément, Nathan Guiraud, Pierre-Luc Mouchel, Marine Dubois, Thomas Farge, Mathilde Gotanègre, Claudie Bosc, et al. “Adrenomedullin-CALCRL Axis Controls Relapse-Initiating Drug Tolerant Acute Myeloid Leukemia Cells.” Nature Communications 12, no. 1 (January 18, 2021): 422. https://doi.org/10.1038/s41467-020-20717-9.
Lopez-Reyes, Rosa G., Grégoire Quinet, Maria Gonzalez-Santamarta, Clément Larrue, Jean-Emmanuel Sarry, and Manuel S. Rodriguez. “Inhibition of the Proteasome and Proteaphagy Enhances Apoptosis in FLT3-ITD-Driven Acute Myeloid Leukemia.” FEBS Open Bio 11, no. 1 (January 2021): 48–60. https://doi.org/10.1002/2211-5463.12950.
Bosc, Claudie, Estelle Saland, Aurélie Bousard, Noémie Gadaud, Marie Sabatier, Guillaume Cognet, Thomas Farge, et al. “Mitochondrial Inhibitors Circumvent Adaptive Resistance to Venetoclax and Cytarabine Combination Therapy in Acute Myeloid Leukemia.” Nature Cancer 2, no. 11 (2021): 1204–23. https://doi.org/10.1038/s43018-021-00264-y.
PUBLICATIONS 2020
Layssol-Lamour, Catherine J., Jean-Emmanuel Sarry, Jean-Pierre D. Braun, Catherine Trumel, and Nathalie H. Bourgès-Abella. “Reference Values for Hematology, Plasma Biochemistry, Bone Marrow Cytology and Bone Histology of NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ Immunodeficient Mice.” Journal of the American Association for Laboratory Animal Science: JAALAS, October 12, 2020. https://doi.org/10.30802/AALAS-JAALAS-20-000020.
Mouchel, Pierre-Luc, Nizar Serhan, Rémy Betous, Thomas Farge, Estelle Saland, Philippe De Medina, Jean-Sébastien Hoffmann, et al. “Dendrogenin A Enhances Anti-Leukemic Effect of Anthracycline in Acute Myeloid Leukemia.” Cancers 12, no. 10 (October 12, 2020): 2933. https://doi.org/10.3390/cancers12102933.
Bories, Pierre, Naïs Prade, Stéphanie Lagarde, Bastien Cabarrou, Laetitia Largeaud, Julien Plenecassagnes, Isabelle Luquet, et al. “Impact of TP53 Mutations in Acute Myeloid Leukemia Patients Treated with Azacitidine.” Edited by Francesco Bertolini. PLOS ONE 15, no. 10 (October 1, 2020): e0238795. https://doi.org/10.1371/journal.pone.0238795.
Stuani, Lucille, and Jean-Emmanuel Sarry. “Microenvironmental Aspartate Preserves Leukemic Cells from Therapy-Induced Metabolic Collapse.” Cell Metabolism 32, no. 3 (September 1, 2020): 321–23. https://doi.org/10.1016/j.cmet.2020.08.008.
Dumas, Pierre-Yves, Sarah Bertoli, Emilie Bérard, Thibaut Leguay, Suzanne Tavitian, Jean Galtier, Camille Alric, et al. “Delivering HDAC over 3 or 5 Days as Consolidation in AML Impacts Health Care Resource Consumption but Not Outcome.” Blood Advances 4, no. 16 (August 25, 2020): 3840–49. https://doi.org/10.1182/bloodadvances.2020002511.
Dumas, Pierre-Yves, Sarah Bertoli, Emilie Bérard, Laetitia Largeaud, Audrey Bidet, Eric Delabesse, Thibaut Leguay, et al. “Real-World Outcomes of Patients with Refractory or Relapsed FLT3-ITD Acute Myeloid Leukemia: A Toulouse-Bordeaux DATAML Registry Study.” Cancers 12, no. 8 (July 24, 2020): 2044. https://doi.org/10.3390/cancers12082044.
Aroua, Nesrine, Emeline Boet, Margherita Ghisi, Marie-Laure Nicolau-Travers, Estelle Saland, Ryan Gwilliam, Fabienne de Toni, et al. “Extracellular ATP and CD39 Activate CAMP-Mediated Mitochondrial Stress Response to Promote Cytarabine Resistance in Acute Myeloid Leukemia.” Cancer Discovery, July 8, 2020, CD-19-1008. https://doi.org/10.1158/2159-8290.CD-19-1008.
Serhan, Nizar, Pierre-Luc Mouchel, Philippe de Medina, Gregory Segala, Aurélie Mougel, Estelle Saland, Arnaud Rives, et al. “Dendrogenin A Synergizes with Cytarabine to Kill Acute Myeloid Leukemia Cells In Vitro and In Vivo.” Cancers 12, no. 7 (June 29, 2020): 1725. https://doi.org/10.3390/cancers12071725.
Vergez, François, Marie-Laure Nicolau-Travers, Sarah Bertoli, Jean-Baptiste Rieu, Suzanne Tavitian, Pierre Bories, Isabelle Luquet, et al. “CD34+CD38−CD123+ Leukemic Stem Cell Frequency Predicts Outcome in Older Acute Myeloid Leukemia Patients Treated by Intensive Chemotherapy but Not Hypomethylating Agents.” Cancers 12, no. 5 (May 6, 2020): 1174. https://doi.org/10.3390/cancers12051174.
Bertoli, Sarah, Pierre-Yves Dumas, Emilie Bérard, Laetitia Largeaud, Audrey Bidet, Eric Delabesse, Suzanne Tavitian, et al. “Outcome of Relapsed or Refractory FLT3-Mutated Acute Myeloid Leukemia before Second-Generation FLT3 Tyrosine Kinase Inhibitors: A Toulouse–Bordeaux DATAML Registry Study.” Cancers 12, no. 4 (March 25, 2020): 773. https://doi.org/10.3390/cancers12040773.
Bertoli, Sarah, Suzanne Tavitian, Emilie Bérard, Véronique Mansat-De Mas, Laetitia Largeaud, Noémie Gadaud, Jean-Baptiste Rieu, et al. “More than Ten Percent of Relapses Occur after Five Years in AML Patients with NPM1 Mutation.” Leukemia & Lymphoma, February 5, 2020, 1–4. https://doi.org/10.1080/10428194.2019.1706733.
Bosc, Claudie, Nicolas Broin, Marjorie Fanjul, Estelle Saland, Thomas Farge, Charly Courdy, Aurélie Batut, et al. “Autophagy Regulates Fatty Acid Availability for Oxidative Phosphorylation through Mitochondria-Endoplasmic Reticulum Contact Sites.” Nature Communications 11, no. 1 (2020): 4056. https://doi.org/10.1038/s41467-020-17882-2.
PUBLICATIONS 2019
Chateauvieux, Sébastien, Anthoula Gaigneaux, Déborah Gérard, Marion Orsini, Franck Morceau, Barbora Orlikova-Boyer, Thomas Farge, et al. “Inflammation Regulates Long Non-Coding RNA-PTTG1-1:1 in Myeloid Leukemia.” Haematologica, October 3, 2019. https://doi.org/10.3324/haematol.2019.217281.
Largeaud, Laetitia, Sarah Bertoli, Emilie Bérard, Stéphanie Dufrechou, Naïs Prade, Noémie Gadaud, Suzanne Tavitian, et al. “Outcome of Relapsed/Refractory AML Patients with IDH1R132 Mutations in Real Life before the Era of IDH1 Inhibitors.” Leukemia & Lymphoma, September 30, 2019, 1–4. https://doi.org/10.1080/10428194.2019.1668937.
Berger, Eloïse, Cyrille Delpierre, Fabien Despas, Sarah Bertoli, Emilie Bérard, Oriane Bombarde, Pierre Bories, et al. “Are Social Inequalities in Acute Myeloid Leukemia Survival Explained by Differences in Treatment Utilization? Results from a French Longitudinal Observational Study among Older Patients.” BMC Cancer 19, no. 1 (September 5, 2019): 883. https://doi.org/10.1186/s12885-019-6093-3.
Hosseini, Mohsen, Hamid Rezvani, Nesrine Aroua, Claudie Bosc, Thomas Farge, Estelle Saland, Véronique Guyonnet-Dupérat, et al. “Targeting Myeloperoxidase Disrupts Mitochondrial Redox Balance and Overcomes Cytarabine Resistance in Human Acute Myeloid Leukemia.” Cancer Research, July 29, 2019. https://doi.org/10.1158/0008-5472.CAN-19-0515.
Stuani, Lucille, and Jean-Emmanuel Sarry. “Help from Outside: Cysteine to Survive in AML.” Blood 134, no. 4 (July 25, 2019): 336–38. https://doi.org/10.1182/blood.2019001580.
Stuani, Lucille, Marie Sabatier, and Jean-Emmanuel Sarry. “Exploiting Metabolic Vulnerabilities for Personalized Therapy in Acute Myeloid Leukemia.” BMC Biology 17, no. 1 (July 18, 2019): 57. https://doi.org/10.1186/s12915-019-0670-4.
Larrue, Clément, Quentin Heydt, Estelle Saland, Héléna Boutzen, Tony Kaoma, Jean-Emmanuel Sarry, Carine Joffre, and Christian Récher. “Oncogenic KIT Mutations Induce STAT3-Dependent Autophagy to Support Cell Proliferation in Acute Myeloid Leukemia.” Oncogenesis 8, no. 8 (July 16, 2019): 39. https://doi.org/10.1038/s41389-019-0148-9.
Boutin, Laetitia, Pierre Arnautou, Aurélie Trignol, Amandine Ségot, Thomas Farge, Christophe Desterke, Sabrina Soave, et al. “Mesenchymal Stromal Cells Confer Chemoresistance to Myeloid Leukemia Blasts through Side Population Functionality and ABC Transporter Activation.” Haematologica, July 9, 2019. https://doi.org/10.3324/haematol.2018.214379.
Bertoli, Sarah, Suzanne Tavitian, Pierre Bories, Isabelle Luquet, Eric Delabesse, Thibault Comont, Audrey Sarry, Françoise Huguet, Emilie Bérard, and Christian Récher. “Outcome of Patients Aged 60-75 Years with Newly Diagnosed Secondary Acute Myeloid Leukemia: A Single-Institution Experience.” Cancer Medicine, June 7, 2019. https://doi.org/10.1002/cam4.2020.
Largeaud, Laetitia, Emilie Bérard, Sarah Bertoli, Stéphanie Dufrechou, Naïs Prade, Noémie Gadaud, Suzanne Tavitian, et al. “Outcome of AML Patients with IDH2 Mutations in Real World before the Era of IDH2 Inhibitors.” Leukemia Research 81 (April 27, 2019): 82–87. https://doi.org/10.1016/j.leukres.2019.04.010.
Bertoli, Sarah, Etienne Paubelle, Emilie Bérard, Estelle Saland, Xavier Thomas, Suzanne Tavitian, Marie-Virginie Larcher, et al. “Ferritin Heavy/Light Chain (FTH1/FTL) Expression, Serum Ferritin Levels, and Their Functional as Well as Prognostic Roles in Acute Myeloid Leukemia.” European Journal of Haematology 102, no. 2 (February 2019): 131–42. https://doi.org/10.1111/ejh.13183.
Bertoli, Sarah, Suzanne Tavitian, Emilie Berard, Noemie Gadaud, Isabelle Luquet, Anne Huynh, Audrey Sarry, Françoise Huguet, and Christian Récher. “Outcome of Relapsed or Refractory Acute Myeloid Leukemia Treated with Intensive Salvage Chemotherapy in Real Life in Comparison to Intermediate Dose Cytarabine in Phase 3 Studies.” Leukemia & Lymphoma 60, no. 1 (2019): 238–41. https://doi.org/10.1080/10428194.2018.1464156.
LES MEMBRES DE L’ÉQUIPE
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Centre de Recherches en Cancérologie de Toulouse (Oncopole)
Toulouse – FR
New study out from the lab on the preclinical characterization of #GeneTherapy for patients with #PancreaticCancer . Thanks to @CHUdeToulouse and @invivogen_US for the wonderful collaboration
https://www.sciencedirect.com/science/article/pii/S2329050123000414
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