Team 9

ChromatIn and transcriptionaL Deregulation in pediatric bone sarcoma

Team leaders : Benjamin Ory et François Lamoureux

Team Child

Our project

The work of our research team is dedicated to understanding the molecular and cellular mechanisms involved in the development of pediatric sarcomas : Rhabdomyosarcoma and primary bone tumors such as Osteosarcoma (OS) and Ewing sarcoma (ES).

French incidence rates from 2012 to 2016 and french survival rate from 2000 to 2016 below. Rhabdomyosarcoma is more present in young children whereas Osteosarcoma and Ewing sarcoma are more present in pre-adolescents. Source



 

Our research program aims in particular to study the epigenetic and transcriptional regulations involved in the development of these pediatric tumors. We focus more particularly on the metastatic dissemination of these cells as well as on their resistance to chemotherapy treatments, which constitute poor prognostic factors in patients.The objective of our work is to identify new therapeutic targets in order to improve the efficiency of the therapeutic management of patients with pediatric sarcomas.

You can see below our two axis of research :

• BET proteins and Super-Enhancers implications in chromatin and transcriptional regulation
• Transcription factor activity and extracellular Stresses

We would like to express our sincere gratitude to France 3 TV for hosting this interview on October 17, 2023. We would also like to extend our appreciation to Imagine for Margo and the Rallye du Coeur, who were both prominently featured in the interview.

• Congratulations to Morgane Lallier who defended her PhD the 08/11/2024 on the role of transcription factor HSF1 in osteosarcoma development and progression.

• Our newest research article Chimeric protein EWS::FLI1 drives cell proliferation in Ewing Sarcoma via aberrant expression of KCNN1/SK1 and dysregulation of calcium signaling is now published! Explore our latest discoveries.

• Check out our lastest review : Super-enhancers: drivers of cells' identities and cells' debacles.

• On the 15th of February 2024 (International Childhood Cancer Day), we have participated in several actions. More on our Linkedin.

• Congratulations to Emma Racineau who got a prize for her poster at the React4kids seminar !

• Professor Ory recently conducted an interview on the topic of sarcoma research. You can watch the video below.

• Congratulations to Maryne Dupuy who defended her PhD the 06/07/2023 on the Epigenetic and transcriptional regulation of KCNN1 and KCNA2 by the EWS-FLI1 fusion protein: role in the control of Ewing's sarcoma cell proliferation.

• Check out our latest article : Tracking Targets of Dynamic Super-Enhancers in Vitro to Better Characterize Osteoclastogenesis and to Evaluate the Effect of Diuron on the Maturation of Human Bone Cells

• Congratulations to Émilien Orgebin who defended his PhD the 26/06/2023 on the Involvement of a variant of the RPL13 protein (eL13) in the development of constitutional bone disease.

• Some members of the team went to the JFBTM from the 22/05/2023 to the 24/05/2023. Morgane Lallier had an oral communication about her work, Maryne Dupuy presented two posters and received a prize.

• Take a look to our latest publication : TRAIL-Based Therapies Efficacy in Pediatric Bone Tumors Models Is Modulated by TRAIL Non-Apoptotic Pathway Activation via RIPK1 Recruitment.

• Congratulations to our Doctors !

  • Louise Marchandet defended her PhD on "Mechanisms of resistance to bromodomain and extra-terminal domain proteins inhibitors in osteosarcoma" the 12th December 2022.

  • Mélanie Lavaud defended her PhD on "Identification of key actors involved in bone tissue development and osteosarcoma progression by studies of active super-enhancers" the 26th October 2022.

  • Robel Tesfaye defended his PhD on "Multi-sample analysis of dynamic super-enhancers to better characterize normal bone development and osteosarcoma evolution" the 19th October 2022.

Faculté de Médecine
1 rue Gaston Veil
44 035 Nantes cedex 1
France
Tel 1 : 02 44 76 91 02
Tel 2 : 02 44 76 91 07

• Microtomograph (or Micro-CT) in vivo Bruker - Skyscan 1276 dedicated to the study of small animals.
• Non-destructive 3D X-ray imaging technique of a sample.
• Software specific to 2D reconstruction, 3D volume rendering, and image analysis.
• Expertise in anatomical exploration : analysis of bone microarchitecture.

Microtomograph 1276 is Property of Nantes Université since october 2021, it is co-funded by FEDER in Région Pays de La Loire and La Ligue contre le Cancer 44.

• Dupuy M, Gueguinou M, Postec A, Brion R, Tesfaye R, Mullard M, Regnier L, Amiaud J, Hubsch C, Potier-Cartereau M, Chantôme A, Brounais-Le Royer B, Baud’huin M, Georges S, Lamoureux F, Ory B, Entz-Werlé N, Delattre O, Rédini F, Vandier C, Verrecchia F. Chimeric protein EWS::FLI1 drives cell proliferation in Ewing Sarcoma via aberrant expression of KCNN1/SK1 and dysregulation of calcium signaling. Oncogene, Nov 2024, 1‑13. doi: https://doi.org/10.1038/s41388-024-03199-7. PMID: 39487324.

• Lavaud M, Tesfaye R, Lassous L, Brounais B, Baud'huin M, Verrecchia F, Lamoureux F, Georges S, Ory B. Super-enhancers: drivers of cells' identities and cells' debacles. Epigenomics, Apr 2024. doi: https://doi.org/10.2217/epi-2023-0409. PMID: 38587919.

• Dupuy M, Gueguinou M, Potier-Cartereau M, Lézot F, Papin M, Chantôme A, Redini F, Vandier C, Verrecchia F. SKCa- and Kv1-type potassium channels and cancer: Promising therapeutic targets ? Biochemical Pharmacology, Sep 2023. doi: https://doi.org/10.1016/j.bcp.2023.115774. PMID: 37678626.

• Dupuy M, Lamoureux F, Mullard M, Postec A, Regnier L, Baud'huin M, Georges S, Brounais-Le Royer B, Ory B, Redini F, Verrecchia F. Ewing sarcoma from molecular biology to the clinic. Front. Cell Dev. Biol., 2023 Sep. doi: https://doi.org/10.3389/fcell.2023.1248753.

• Tesfaye R, Lavaud M, Charrier C, Brounais-Le Royer B, Cartron PF, Verrecchia F, Baud'huin M, Lamoureux F, Georges S, Ory B. Tracking Targets of Dynamic Super-Enhancers in Vitro to Better Characterize Osteoclastogenesis and to Evaluate the Effect of Diuron on the Maturation of Human Bone Cells. Environ Health Perspect. 2023 Jun; 131(6): 067007. doi: https://doi.org/10.1289/EHP11690. PMID: 37307168. PMCID: PMC10259763.

• Brion R, Gantier M, Biteau K, Taurelle J, Brounais-Le Royer B, Verrecchia F, Rédini F, Guiho R. TRAIL-Based Therapies Efficacy in Pediatric Bone Tumors Models Is Modulated by TRAIL Non-Apoptotic Pathway Activation via RIPK1 Recruitment. Cancers (Basel). 2022 Nov 16;14(22):5627. doi: 10.3390/cancers14225627. PMID: 36428719; PMCID: PMC9688679.

• Moukengue B, Lallier M, Marchandet L, Baud'huin M, Verrecchia F, Ory B, Lamoureux F. Origin and Therapies of Osteosarcoma. Cancers (Basel). 2022 Jul 19;14(14):3503. doi: 10.3390/cancers14143503. PMID: 35884563; PMCID: PMC9322921.

• Rodriguez Calleja L, Lavaud M, Tesfaye R, Brounais-Le-Royer B, Baud'huin M, Georges S, Lamoureux F, Verrecchia F, Ory B. The p53 Family Members p63 and p73 Roles in the Metastatic Dissemination: Interactions with microRNAs and TGFβ Pathway. Cancers (Basel). 2022 Dec 1;14(23):5948. doi: 10.3390/cancers14235948. PMID: 36497429; PMCID: PMC9741383.

• Crenn V, Amiaud J, Gomez-Brouchet A, Potiron V, Gouin F, Rosset P, Nail LL, Vidal L, Bertin H, Brion R, Tran G, Verrecchia F, Corre I, Redini F. Signature of the vascular tumor microenvironment as a marker of the therapeutic response to doxorubicin in a preclinical model of osteosarcoma. Am J Cancer Res. 2022 Apr 15;12(4):1843-1854. PMID: 35530297; PMCID: PMC9077066.

• Marchais A, Marques da Costa ME, Job B, Abbas R, Drubay D, Piperno-Neumann S, Fromigué O, Gomez-Brouchet A, Redini F, Droit R, Lervat C, Entz-Werle N, Pacquement H, Devoldere C, Cupissol D, Bodet D, Gandemer V, Berger M, Marec-Berard P, Jimenez M, Vassal G, Geoerger B, Brugières L, Gaspar N. Immune Infiltrate and Tumor Microenvironment Transcriptional Programs Stratify Pediatric Osteosarcoma into Prognostic Groups at Diagnosis. Cancer Res. 2022 Mar 15;82(6):974-985. doi: 10.1158/0008-5472.CAN-20-4189. PMID: 35078815.

• Veys C, Jammes M, Rédini F, Poulain L, Denoyelle C, Legendre F, Galera P. Tumor Suppressive Role of miR-342-5p and miR-491-5p in Human Osteosarcoma Cells. Pharmaceuticals (Basel). 2022 Mar 16;15(3):362. doi: 10.3390/ph15030362. PMID: 35337159; PMCID: PMC8949568.

• Nazon C, Pierrevelcin M, Willaume T, Lhermitte B, Weingertner N, Marco AD, Bund L, Vincent F, Bierry G, Gomez-Brouchet A, Redini F, Gaspar N, Dontenwill M, Entz-Werle N. Together Intra-Tumor Hypoxia and Macrophagic Immunity Are Driven Worst Outcome in Pediatric High-Grade Osteosarcomas. Cancers (Basel). 2022 Mar 14;14(6):1482. doi: 10.3390/cancers14061482. PMID: 35326631; PMCID: PMC8945994.

• Muñoz-Garcia J, Vargas-Franco JW, Royer BB, Cochonneau D, Amiaud J, Heymann MF, Heymann D, Lézot F. Inhibiting Endothelin Receptors with Macitentan Strengthens the Bone Protective Action of RANKL Inhibition and Reduces Metastatic Dissemination in Osteosarcoma. Cancers (Basel). 2022 Mar 30;14(7):1765. doi: 10.3390/cancers14071765. PMID: 35406536; PMCID: PMC8997105.

• Marchandet L, Lallier M, Charrier C, Baud'huin M, Ory B, Lamoureux F. Mechanisms of Resistance to Conventional Therapies for Osteosarcoma. Cancers (Basel). 2021 Feb 8;13(4):683. doi: 10.3390/cancers13040683. PMID: 33567616; PMCID: PMC7915189.

• Lallier M, Marchandet L, Moukengue B, Charrier C, Baud'huin M, Verrecchia F, Ory B, Lamoureux F. Molecular Chaperones in Osteosarcoma: Diagnosis and Therapeutic Issues. Cells. 2021 Mar 30;10(4):754. doi: 10.3390/cells10040754. PMID: 33808130; PMCID: PMC8067202.

• Mullard M, Lavaud M, Regnier L, Tesfaye R, Ory B, Rédini F, Verrecchia F. Ubiquitin-specific proteases as therapeutic targets in paediatric primary bone tumours? Biochem Pharmacol. 2021 Dec;194:114797. doi: 10.1016/j.bcp.2021.114797. Epub 2021 Oct 19. PMID: 34678225.

• Morice S, Danieau G, Tesfaye R, Mullard M, Brion R, Dupuy M, Ory B, Brounais-Le Royer B, Corre I, Redini F, Verrecchia F. Involvement of the TGF-β Signaling Pathway in the Development of YAP-Driven Osteosarcoma Lung Metastasis. Front Oncol. 2021 Oct 26;11:765711. doi: 10.3389/fonc.2021.765711. PMID: 34765560; PMCID: PMC8576330.

• Lavaud M, Mullard M, Tesfaye R, Amiaud J, Legrand M, Danieau G, Brion R, Morice S, Regnier L, Dupuy M, Brounais-Le Royer B, Lamoureux F, Ory B, Rédini F, Verrecchia F. Overexpression of the Ubiquitin Specific Proteases USP43, USP41, USP27x and USP6 in Osteosarcoma Cell Lines: Inhibition of Osteosarcoma Tumor Growth and Lung Metastasis Development by the USP Antagonist PR619. Cells. 2021 Aug 31;10(9):2268. doi: 10.3390/cells10092268. PMID: 34571917; PMCID: PMC8464711.

• Brion R, Regnier L, Mullard M, Amiaud J, Rédini F, Verrecchia F. LIM Kinases in Osteosarcoma Development. Cells. 2021 Dec 15;10(12):3542. doi: 10.3390/cells10123542. PMID: 34944050; PMCID: PMC8699892.

• Danieau G, Morice S, Renault S, Brion R, Biteau K, Amiaud J, Cadé M, Heymann D, Lézot F, Verrecchia F, Rédini F, Brounais-Le Royer B. ICG-001, an Inhibitor of the β-Catenin and cAMP Response Element-Binding Protein Dependent Gene Transcription, Decreases Proliferation but Enhances Migration of Osteosarcoma Cells. Pharmaceuticals (Basel). 2021 May 1;14(5):421. doi: 10.3390/ph14050421. PMID: 34062831; PMCID: PMC8147379.

• Moniot A, Braux J, Bour C, Guillaume C, Lamret F, Allart-Simon I, Audonnet S, Renault S, Rédini F, Laronze-Cochard M, Sapi J, Gangloff SC, Gérard S, Velard F. Pyridazinone Derivatives Limit Osteosarcoma-Cells Growth In Vitro and In Vivo. Cancers (Basel). 2021 Nov 28;13(23):5992. doi: 10.3390/cancers13235992. PMID: 34885102; PMCID: PMC8656549.

• Gomez-Brouchet A, Gilhodes J, Acker NV, Brion R, Bouvier C, Assemat P, Gaspar N, Aubert S, Guinebretiere JM, Marie B, Larousserie F, Entz-Werlé N, Pinieux G, Mascard E, Gouin F, Brousset P, Tabone MD, Jimenez M, Le Deley MC, Blay JY, Brugieres L, Piperno-Neumann S, Rédini F. Characterization of Macrophages and Osteoclasts in the Osteosarcoma Tumor Microenvironment at Diagnosis: New Perspective for Osteosarcoma Treatment? Cancers (Basel). 2021 Jan 23;13(3):423. doi: 10.3390/cancers13030423. PMID: 33498676; PMCID: PMC7866157.

• Combal A, Thuau F, Fouasson-Chailloux A, Arrigoni PP, Baud'huin M, Duteille F, Crenn V. Preliminary Results of the "Capasquelet" Technique for Managing Femoral Bone Defects-Combining a Masquelet Induced Membrane and Capanna Vascularized Fibula with an Allograft. J Pers Med. 2021 Aug 9;11(8):774. doi: 10.3390/jpm11080774. PMID: 34442418; PMCID: PMC8401617.

• Moukengue B, Brown HK, Charrier C, Battaglia S, Baud'huin M, Quillard T, Pham TM, Pateras IS, Gorgoulis VG, Helleday T, Heymann D, Berglund UW, Ory B, Lamoureux F. TH1579, MTH1 inhibitor, delays tumour growth and inhibits metastases development in osteosarcoma model. EBioMedicine. 2020 Mar;53:102704. doi: 10.1016/j.ebiom.2020.102704. Epub 2020 Mar 7.

• Briand J, Sérandour AA, Nadaradjane A, Bougras-Cartron G, Heymann D, Ory B, Vallette FM, Cartron PF. N6-Adenosine Methylation of miRNA-200b-3p Influences Its Functionality and Is a Theranostic Tool. Mol Ther Nucleic Acids. 2020 Aug 14;22:72-83. doi: 10.1016/j.omtn.2020.08.010. PMID: 32916600; PMCID: PMC7490450.

• Cheray M, Etcheverry A, Jacques C, Pacaud R, Cartron G, Denoual F, Aubry M, Nadaradjane A, Heymann D, Vallette FM, Mosser J, Ory B and Cartron PF. Cytosine methylation of mature microRNAs inhibits their functions and is associated with poor prognosis in glioblastoma multiforme. Molecular Cancer. 2020. Accepté le 7-02-2020. MOLC-D-19-01811R1. doi: 10.1186/s12943-020-01155-z. PMID: 32098627; PMCID: PMC7041276.

• Gama A, Vargas-Franco JW, Sánchez Mesa DC, Restrepo Bedoya E, Amiaud J, Babajko S, Berdal A, Acevedo AC, Heymann D, Lézot F, Castaneda B. Origins of Alterations to Rankl Null Mutant Mouse Dental Root Development. Int J Mol Sci 2020;21(6). doi: 10.3390/ijms21062201. PMID: 32209985; PMCID: PMC7139335.

• Gama A, Maman L, Vargas-Franco JW, Omar R, Brounais-Le Royer B, Yagita H, Babajko S, Berdal A, Acevedo AC, Heymann D, Lézot F*, Castaneda B*. Primary Retention of Molars and RANKL Signaling Alteration during Craniofacial Growth. J Clin Med 2020;9(4). doi: 10.3390/jcm9040898. PMID: 32218136; PMCID: PMC7231205.

• Najm A, Masson FM, Preuss P, Georges S, Ory B, Quillard T, Sood S, Goodyear CS, Veale DJ, Fearon U, Le Goff B, Blanchard F. miR-17-5p reduces inflammation and bone erosions in collagen induced arthritis mice and directly targets the JAK-STAT pathway in rheumatoid arthritis fibroblast-like synoviocytes. Arthritis Rheumatol. 2020 Jul 19. doi: 10.1002/art.41441. PMID: 32683798.

• Orgebin E, Lamoureux F, Isidor B, Charrier C, Ory B, Lézot F, Baud'huin M. Ribosomopathies: New Therapeutic Perspectives. Cells. 2020 Sep 11;9(9):E2080. doi: 10.3390/cells9092080. PMID: 32932838; PMCID: PMC7564184.

• Morice S, Danieau G, Rédini F, Brounais-Le-Royer B, Verrecchia F. Hippo/YAP Signaling Pathway: A Promising Therapeutic Target in Bone Paediatric Cancers? Cancers (Basel). 2020;12(3):645. doi: 10.3390/cancers12030645. PMID: 32164350; PMCID: PMC7139637.

• Lézot F, Corre I, Morice S, Rédini F, Verrecchia F. SHH Signaling Pathway Drives Pediatric Bone Sarcoma Progression. Cells. 2020;9(3):536. doi: 10.3390/cells9030536. PMID: 32110934; PMCID: PMC7140443.

• Corre I, Verrecchia F, Crenn V, Rédini F and Trichet V. The osteosarcoma microenvironment: A complex but targetable ecosystem. Cells 2020 ; 9:976. doi: 10.3390/cells9040976. PMID: 32326444. PMCID: PMC7226971.

• Jacques C, Tesfaye R, Lavaud M, Georges S, Baud'huin M, Lamoureux F, Ory B.Implication of the p53- Related miR-34c, -125b, and -203 in the Osteoblastic Differentiation and the Malignant Transformation of Bone Sarcomas. Cells. 2020 Mar 27;9(4). pii: E810. doi: 10.3390/cells9040810. PMID: 32230926; PMCID: PMC7226610.

• Grünewald TGP, Alonso M, Avnet S, Banito A, Burdach S, Cidre-Aranaz F, Di Pompo G, Distel M, DoradoGarcia H, Garcia-Castro J, González-González L, Grigoriadis AE, Kasan M, Koelsche C, Krumbholz M, Lecanda F, Lemma S, Longo DL, Madrigal-Esquivel C, Morales-Molina A, Musa J, Ohmura S, Ory B, Pereira-Silva M, Perut F, Rodriguez R, Seeling C, Al Shaaili N, Shaabani S, Shiavone K, Sinha S, Tomazou EM, Trautmann M, Vela M, Versleijen-Jonkers YMH, Visgauss J, Zalacain M, Schober SJ, Lissat A, English WR, Baldini N*, and Heymann D*. Sarcoma treatment in the era of molecular medicine. EMBO, 2020. doi: 10.15252/emmm.201911131. PMID: 33047515; PMCID: PMC7645378.

• Talbot J, Dupuy M, Morice S, Rédini F, Verrecchia F. Antagonistic Functions of Connexin 43 during the Development of Primary or Secondary Bone Tumors. Biomolecules. 2020 Aug 26;10(9):E1240. doi: 10.3390/biom10091240. PMID: 32859065; PMCID: PMC7565206.

• Morice S, Mullard M, Brion R, Dupuy M, Renault S, Tesfaye R, Brounais-Le Royer B, Ory B, Redini F, Verrecchia F. The YAP/TEAD Axis as a New Therapeutic Target in Osteosarcoma: Effect of Verteporfin and CA3 on Primary Tumor Growth.Cancers (Basel). 2020 Dec 20;12(12):3847. doi: 10.3390/cancers12123847. PMID: 33419295; PMCID: PMC7766439.

• Mullard M, Cadé M, Morice S, Dupuy M, Danieau G, Amiaud J, Renault S, Lézot F, Brion R, Thepault RA, Ory B, Lamoureux F, Corre I, Brounais-LeRoyer B, Rédini F, Verrecchia F. Sonic Hedgehog Signature in Pediatric Primary Bone Tumors: Effects of the GLI Antagonist GANT61 on Ewing's Sarcoma Tumor Growth. Cancers (Basel). 2020 Nov 19;12(11):3438. doi: 10.3390/cancers12113438. PMID: 33228057; PMCID: PMC7699338.

• Tabti R, Lamoureux F, Charrier C, Ory B, Heymann D, Bentouhami E, Désaubry L. Development of prohibitin ligands against osteoporosis. Eur J Med Chem. 2020 Oct 23:112961. doi: 10.1016/j.ejmech.2020.112961. PMID: 33129591.

• Jacques C, Lavaud M, Georges S, Tesfaye R, Baud'huin M, Lamoureux F, Ory B. BET bromodomains' functions in bone-related pathologies. Epigenomics. 2020 Jan;12(2):127-144. doi: 10.2217/epi-2019-0172. PMID: 31849242.