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    Functional characterization and therapeutic targeting of NF1 driven tumors

    Principal Investigator

    Eric Pasmant
    Contact: eric.pasmant@parisdescartes.fr

     

    Objective

    NF1 is a tumor predisposition syndrome resulting from constitutional heterozygous mutations of the NF1 gene encoding neurofibromin, a RAS-MAPK pathway inhibitor. NF1 patients have an increased risk for malignant and non-malignant tumors compared with the general population. At present, no definitive treatment is available, and clinical management is typically limited to surveillance and symptomatic treatment, usually surgical, for specific complications. We aim to perform functional characterization of NF1 driven tumors, including genomic approaches in leukocyte and tumor samples from NF1 patients, and functional approaches in primary and tumor cell lines, and in genetically modified cells.

     

    The group

    • Manuela Yé (Post-Doc)
    • Camille Tlemsani (MCU-PH, Université de Paris)
    • Ivan Bièche (PU-PH, Université de Paris)
    • Dominique Vidaud (MCU-PH, Université de Paris)
    • Ingrid Laurendeau (IE, Université de Paris)

     

    Research interests

    Neurofibromas are one of the major clinical features of NF1. They are benign peripheral nerve sheath tumors which consist in a proliferation of Schwann cells showing somatic inactivation of the NF1 WT allele. The malignant transformation of neurofibromas into MPNSTs (Malignant Peripheral Nerve Sheath Tumors) is the leading cause of death in NF1 patients. In 2014, we demonstrated for the first time that PRC2 (Polycomb Repressive Complex 2) played a key role in the development of NF1-associated MPNSTs, in an international collaborative study (De Readt et al. 2014). PRC2 is involved in maintaining transcriptional repression. EZH1/2, the catalytic PRC2 components, function as histone methyltransferase that di- and tri-methylates lysine 27 on histone 3 (H3K27me3). EED, SUZ12 and RBBP4/7 are required for complete function and stability of the PRC2 complex.

    In collaboration with Raphaël Margueron’s team (Institut Curie), we aim to search for signaling pathways which are altered consequently to PRC2 mutations in MPNSTs. Spatial transcriptomics innovative approaches will be implemented to study the intra-tumoral heterogeneity of MPNSTs presenting mutations of the transcriptional repressor PRC2. In addition, we have selectively inactivated the PRC2 in Schwann cells immortalized from NF1-associated neurofibromas, using CRISPR Cas9 genomic editing techniques. We will use our genetically modified cell lines to ask how specific cell properties are affected by the lack of PRC2. By comparing PRC2 wild-type and mutant isogenic cell lines, these experiments should allow us to assess the contribution of PRC2 alteration to the malignant evolution of NF1 deficient cells, as well as the signaling pathways that could be targeted for therapy. In order to identify vulnerabilities associated with PRC2 mutations, two approaches will be used: chemical and genetic screens. We hope that these approaches will open new avenues to target MPNSTs. The same strategies will also be used to target the complete loss of function of the NF1 gene, that occurs in NF1-associated tumors.

    In addition to nerve sheath tumors, our team is also interested in optic pathway gliomas associated with NF1. Our goal is to understand the molecular basis of glioma development in NF1 by studying the genetic alterations at the origin of tumor development.

     

    Main publications

    • Vairy S, Le Teuff G, Bautista F, De Carli E, Bertozzi AI, Pagnier A, Fouyssac F, Nysom K, Aerts I, Leblond P, Millot F, Berger C, Canale S, Paci A, Poinsignon V, Chevance A, Ezzalfani M, Vidaud D, Di Giannatale A, Hladun-Alvaro R, Petit FM, Vassal G, Geoerger B, Le Deley MC, Grill J. Phase I study of vinblastine in combination with nilotinib in children, adolescents, and young adults with refractory or recurrent low-grade glioma. Neurooncol Adv. 2020;2(1):vdaa075.
    • Wassef M, Luscan A, Aflaki S, Zielinski D, Jansen PWTC, Baymaz HI, Battistella A, Kersouani C, Servant N, Wallace MR, Romero P, Kosmider O, Just PA, Hivelin M, Jacques S, Vincent-Salomon A, Vermeulen M, Vidaud M, Pasmant E*, Margueron R*. EZH1/2 function mostly within canonical PRC2 and exhibit proliferation-dependent redundancy that shapes mutational signatures in cancer. Proc Natl Acad Sci U S A. 2019;116(13):6075-6080. *corresponding authors
    • Wassef M, Pasmant E, Margueron R. MPNST Epigenetics. Mol Cancer Res. 2019;17(10):2139.
    • Lobón-Iglesias MJ, Laurendeau I, Guerrini-Rousseau L, Tauziède-Espariat A, Briand-Suleau A, Varlet P, Vidaud D, Vidaud M, Brugieres L, Grill J, Pasmant E. NF1-like optic pathway gliomas in children: clinical and molecular characterization of this specific presentation. Neurooncol Adv. 2019;2:i98-i106.
    • D'Angelo F, Ceccarelli M, Tala, Garofano L, Zhang J, Frattini V, Caruso FP, Lewis G, Alfaro KD, Bauchet L, Berzero G, Cachia D, Cangiano M, Capelle L, de Groot J, DiMeco F, Ducray F, Farah W, Finocchiaro G, Goutagny S, Kamiya-Matsuoka C, Lavarino C, Loiseau H, Lorgis V, Marras CE, McCutcheon I, Nam DH, Ronchi S, Saletti V, Seizeur R, Slopis J, Suñol M, Vandenbos F, Varlet P, Vidaud D, Watts C, Tabar V, Reuss DE, Kim SK, Meyronet D, Mokhtari K, Salvador H, Bhat KP, Eoli M, Sanson M, Lasorella A, Iavarone A. The molecular landscape of glioma in patients with Neurofibromatosis 1. Nat Med. 2019;25(1):176-187.
    • Campagne A, Lee MK, Zielinski D, Michaud A, Le Corre S, Dingli F, Chen H, Shahidian LZ, Vassilev I, Servant N, Loew D, Pasmant E, Postel-Vinay S, Wassef M, Margueron R. BAP1 complex promotes transcription by opposing PRC1-mediated H2A ubiquitylation. Nat Commun. 2019 Jan 21;10(1):348.
    • Shackleford G, Sampathkumar NK, Hichor M, Weill L, Meffre D, Juricek L, Laurendeau I, Chevallier A, Ortonne N, Larousserie F, Herbin M, Bièche I, Coumoul X, Beraneck M, Baulieu EE, Charbonnier F, Pasmant E, Massaad C. Involvement of Aryl hydrocarbon receptor in myelination and in human nerve sheath tumorigenesis. Proc Natl Acad Sci U S A. 2018;115:E1319-E1328.
    • Sohier P, Luscan A, Lloyd A, Ashelford K, Laurendeau I, Briand-Suleau A, Vidaud D, Ortonne N, Pasmant E, Upadhyaya M. Confirmation of mutation landscape of NF1-associated malignant peripheral nerve sheath tumors. Genes Chromosomes Cancer 2017;56(5):421-426.
    • Pasmant E, Sohier P, Larousserie F. Synovial Sarcomas Do Not Show H3K27 Trimethylation Loss Using Immunohistochemistry. Am J Surg Pathol. 2017;41(2):283-285.
    • De Raedt T, Beert E*, Pasmant E*, Luscan A, Brems H, Ortonne N, Helin K, Hornick JL, Mautner V, Kehrer-Sawatzki H, Clapp W, Bradner J, Vidaud M, Upadhyaya M, Legius E, Cichowski K. PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature 2014;514:247-51. *equal contribution
    • Luscan A, Shackleford G, Masliah-Planchon J, Laurendeau I, Ortonne N, Varin J, Lallemand F, Leroy K, Dumaine V, Hivelin M, Borderie D, De Raedt T, Valeyrie-Allanore L, Larousserie F, Terris B, Lantieri L, Vidaud M, Vidaud D, Wolkenstein P, Parfait B, Bieche I, Massaad C, Pasmant E. The activation of the WNT signaling pathway is a Hallmark in neurofibromatosis type 1 tumorigenesis. Clin Cancer Res. 2014;20:358-71.

     

    Financial supports

    The project to identify synthetic lethality with NF1 loss-of-function has been supported since 2019 by The Gilbert Family Foundation's Gene Therapy Initiative.

    The CARPEM Projet Innovation 2020 grant supports the development of spatial transcriptomic approaches for the study of intra-tumoral heterogeneity of malignant nerve sheaths tumors with mutations in the transcriptional repressor PRC2.

    The Projet Émergence en Recherche 2020 of IdEx Université de Paris supports the study of the LXRβ pathway for new treatments of neurofibromas.