TEAM
Jean-EMMANUEL SARRY

METAML :

Metabolism and Therapeutic Resistance In
Acute Myeloid Leukemia

The Toulouse Cancer Laboratory of Excellence is a project that aims to understand the genetic and non-genetic mechanisms of resistance and relapse in cancer.

the specifities

of our research axis

Acute Myeloid Leukemia (AML) is a heterogeneous group of hematological malignancies resulting from the transformation of hematopoietic progenitors. Therapeutic resistance is the major reason of recurrence in AML patients and represents the main consequence of their unfavorable prognosis. The METAML team has shown that this resistance is initiated by cells whose mitochondria have a very high energy and oxidative activity (“OxPHOS”) after conventional chemotherapy but also after newly approved targeted therapies. We also demonstrated that this high mitochondrial activity is due to a metabolic adaptation set up by AML cells in response to mitochondrial stresses induced by the treatments. This leads to an increase in catabolic, energetic and reactive oxygen species (ROS) detoxification capacities, to a high flexibility to use different nutrients and to a greater dependence on mitochondrial NADH dehydrogenases (in particular NADH dehydrogenase of the respiratory chain complex I) Our studies have led to the filing of several patents on new molecular targets (e.g. CD39, CALCRL, ADM) whose inhibition allows sensitization of chemotherapy-resistant cells. More recently, our research has also led us to study the role of metabolic dialogue within the tumor and the host (JE. Sarry), transcriptional regulation and RNA splicing (M. Ghisi), as well as leukemic and host autophagy (C. Joffre) in the adaptive and metabolic mechanisms of therapeutic resistance. All this work is done in a strong preclinical (mouse and xenograft models with CREFRE; diets with ENVT, F. Granat) and clinical context in AML patients (S. Bertoli, V. DeMas, O. Rauzy, C. Récher, F. Vergez).

Acute myeloid leukemia

Metabolism and mitochondria

Therapeutic resistance

Oxidative stress

Metabolic adaptation

Leukemic microenvironment

Tumor heterogeneity

Transcriptional and post-transcriptional regulation

Autophagy

Signaling

RESEARCH PROJECTS

THE TEAM’S
FOCUS

SCIENTIFIC PRODUCTIONS

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.

TEAM MEMBERS

Loïc Platteeuw
Doctorant / PhD student
Nathaniel Polley
Doctorant / PhD student
Odile Rauzy
Enseignant chercheur / University researcher
Thibault Comont
Doctorant / PhD student
François Vergez
Enseignant chercheur / University researcher
Jean-Emmanuel Sarry
Chercheur statutaire / permanent scientist
Margaux Oberling
Doctorant / PhD student
Mathieu Landry
Ingénieur de laboratoire / laboratory engineer
Véronique DE MAS
Clinicien Chercheur / Researcher hospital practitioner
Margherita Ghisi
Chercheur statutaire / permanent scientist
Guillaume Cognet
Doctorant / PhD student
Marie Sabatier
Chercheur Post-Doctorant / Post-Doc researcher
Emeline Boet
Doctorant / PhD student
Nathan Guiraud
Doctorant / PhD student
Carine Joffre
Chercheur statutaire / permanent scientist
Laura Lauture
Doctorant / PhD student
Latifa Jarrou
Technicien de laboratoire / Laboratory Technician
Charlotte DUCAU
Doctorant / PhD student

PARTERNSHIPS & FUNDING

Centre de Recherches en Cancérologie de Toulouse

Centre de Recherches en Cancérologie de Toulouse (Oncopole)

Toulouse – FR

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05 82 74 15 75

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