CONTACT

Franck Tirode, DR2 INSERM
Team Leader
franck.tirode@lyon.unicancer.fr
BRAHMI Mehdi
Oncologue médical CLB, doctorant
mehdi.brahmi@lyon.unicancer.fr
DUC-GALLET Adeline
Technicienne Hautement Qualifiée CLB
adeline.duc@lyon.unicancer.fr
GALATEAU-SALLE Françoise
GANIVET Quentin

Etudiant M2 bioinformatique
quentin.ganivet@lyon.unicancer.fr

KARANIAN Marie
Pathologiste CLB, doctorante
marie.karanian@lyon.unicancer.fr
LANGRY Marine
Technicienne spécialisée CLB
marine.langry@lyon.unicancer.fr
PERRIN Virginie
IE CLB, Responsable opértionnel
virginie.perrin@lyon.unicancer.fr
PISSALOUX Daniel
Igénieur biologiste CLB
daniel.pissaloux@lyon.unicancer.fr
RIFAI Khaldoun
Voir les objectifs et projets Voir les publications

Collaborations :
Nadège Corradini, Centre Léon Bérard (Lyon)
Olivier Delattre, Institut Curie (Paris)
François Le Loarer, Institut Bergonié (Bordeaux)
Katia Scotlandi (Istituto Ortopedico Rizzoli, Italie)
James Amatruda, Los Angeles Children hospital (USA)


Financial supports:
Institut National du Cancer
Fondation ARC
Centre Léon Bérard

OBJECTIVES

Sarcomas form an heterogeneous group of aggressive malignant tumors of mesenchymal origin. They affect about 4000 people a year in France and are rather bad prognosis. Despite their relatively low numbers in adults, sarcomas account for more than 20% of cancer-related deaths in children and young adults. Because of their great heterogeneity (more than 50 different histological types and more than 150 molecular subtypes) the precise diagnosis of sarcomas is often difficult to pose, leading to difficulties in their therapeutic management. With the event of high throughput sequencing, the identification of new alterations has significantly improved the diagnosis and provided insights into oncogenic mechanisms. Thus, nearly 30% of sarcomas have a fusion gene directly responsible for the tumor development. However, a significant proportion of sarcomas remain uncharacterized, with no oncogenic events and / or distinct biomarkers, constituting a major diagnostic and therapeutic challenge.

Our team aims to:

1) Reach a molecular characterization of sarcomas as complete as possible,
2) Functionally study the most recurrent alterations identified in aim 1, in order to discover new oncogenic mechanisms,
3) To identify genes, epigenetic modifications or signaling pathways mandatory for tumor growth, allowing the development of innovative targeted therapeutic approaches.

PROJECTS

Molecular classification of sarcomas:

In close collaboration with the Department of Pathology of the Léon Bérard Center we undertook a molecular classification of sarcomas using high-throughput RNA sequencing from paraffin-preserved tumor sample. From this sequencing we can determine for each sample the presence of fusion genes, the expression profile - whose specific immune profiles - and coding nucleotide variants, which we relate to clinical and pathological data. In particular, the accumulation of several thousand tumor expression profiles, allows us, by unsupervised methods and / or learning, to classify the tumor samples (Figure 1). This strategy has already enabled us to highlight new tumor subtypes, such as SMARCA4-deficient thoracic sarcomas (Le Loarer F. et al, 2014, Perret, R et al., 2018), EWSR1 / FUS fusion rhabdomyosarcomas -TFCP2 (Watson et al., 2018, Loarer, F. et al., 2019), or CRTC1-SS18 translocated small-cell sarcomas (Alholle et al, 2019). These analyzes are also conducted for other cancerous pathologies such as melanoma tumors (in collaboration with Dr. Arnaud de Fouchardière, CLB) and mesothelioma (Dr. Françoise Galateau-Sallé, CLB). Finally, within our iMAPS project (INCa-DGOS_13219), we undertake an integrative analysis of unclassified pediatric sarcomas by studying not only their gene expression but also their methylome and exome.

Figure 1 : Unsupervised analysis (t-SNE) of tumors expression profiles showing the clustering of samples (represented by spheres) 
by tumor sub-types (represented by different colrors).


Functional studies of the fusion proteins found in sarcomas.

In the recent years, many new fusion genes, the oncogenes responsible for the tumor development, have been identified, in sarcomas in particular. Among these, we focused in those observed the most frequently and/or which are not or little studied. Thanks to the molecular characterization described above, we identified some recurrent gene fusions, which are not described yet in the literature, that we functionally investigate. In particular, we are most interested in the function of the CIC-DUX4 and HEY1-NCOA2 fusion genes as well as of the rearranged BCOR gene, which only benefited of scarce investigations, in ectopic cellular models.  Through the development of specific cellular models (in collaboration with the teams of Olivier Delattre, Katia Scotlandi and James Amatruda), we are in position to study thes oncoproteins in their native cellular context. Their inhibitions in relevant cellular models allow us to determine, in ChIP-seq experiments, co-immunoprecipitation followed by mass spectrometry and RNA-seq, their direct targets as well as their protein partners. We are also investigating signaling pathways that may be deregulated in these tumors, in order to identify potential therapeutic targets which we may then hit in our in vivo models.

Figure 2: ChIP-seq showing a CIC-DUX4 binding site in a promoter region (positive for enhancer marks H3K4me3 and H3K27Ac).


Role of epigenetics in sarcomas’ oncogenesis

Initiation and progression of cancer are controlled by both genetic and epigenetic events. Unlike genetic modifications, epigenetic aberrations are reversible, which may then theoretically restore the epigenetic state of a malignant cell to its pre-malignant state. Moreover, we were able to establish that many of these translocation positive sarcomas have a transcriptomic profile evocative of a defect in a chromatin remodeling complex and more generally in an epigenetic mechanism. We are particularly interested in the dysregulation of epigenetic mechanisms in BCOR-rearranged sarcomas and in endometrial stromal sarcomas with BCOR (or an assimilated gene) alteration, BCOR being a member of the PRC1.1 chromatin repressive complex. We are also interested in the roles of the SIRT1 and KAT5 proteins, which are possible effectors of the PRC1.1 complex during epigenetic repression.

PUBLICATIONS

2019

Le Loarer, F., Pissaloux, D., Watson, S., Godfraind, C., Galmiche-Rolland, L., Silva, K., Mayeur, L., Italiano, A., Michot, A., Alberti, L., Pierron, G., Vasiljevic, A., Ranchere-Vince, D., Coindre, J.M. and Tirode, F. (2019). Clinicopathological features of CIC-NUTM1 sarcomas, a new molecular variant of the family of CIC-fused sarcomas. Am J Surg Pathol. 43(2),268–276

Perret, R., Chalabreysse, L., Watson, S., Serre, I., Garcia, S, Forest, F, Yvorel, V., Pissaloux, D., Thomas de Montpreville, V., Masliah-planchon, J., Lantuejoul, S.,  Brevet, M., Blay, J.Y., Coindre, J. M., Tirode, F., Le Loarer, F. (2019) SMARCA4-deficient thoracic sarcomas: clinicopathologic study of 30 cases with an emphasis on their nosology and differential diagnosis. Am J Surg Pathol, 43(4):455-465

Le Loarer F., Laffont S., Lesluyes T., Tirode F., Antonescu C., Baglin A.-C., Delespaul L., Soubeyran I., Hostein I., Pérot G., Chibon F., Baud J., Guellec S.L., Karanian M., Costes-Martineau V., Castain C., Eimer S., Bail B.L., Wassef M., Coindre J.-M. (2019) Clinicopathologic and Molecular Features of a Series of 41 Biphenotypic Sinonasal Sarcomas Expanding Their Molecular Spectrum. Am J Surg Pathol. 43(6), 747–754

Carbonnaux M, Brahmi M, Schiffler C, Meeus P, Sunyach M.P, Bouhamama A., Karanian M., Tirode F.,Pissaloux D., Vaz, G.,  Ray‐Coquard I., Blay J.Y, Dufresne A. (2019) Very long‐term survivors among patients with metastatic soft tissue sarcoma. Cancer Med. 2018;00:1–11

Baltres A., Salhi A., Houlier A., Pissaloux D., Tirode F., Haddad V., Karanian M., Ysmail Dahlouk S., Boukendakdji F., Dahlouk D., Allaoua F., Metref M., Djeridane A., Fraitag S., de la Fouchardiere A. (2019 ) Malignant melanoma with areas of rhabdomyosarcomatous differentiation arising in a giant congenital nevus with RAF1 gene fusion. Pigment Cell Melanoma Res. Apr 4. doi: 10.1111/pcmr.12785. [Epub ahead of print]

Goto K., Pissaloux D., Paindavoine P., Tirode F., de la Fouchardière A. (2019) CYSLTR2-mutant Cutaneous Melanocytic Neoplasms Frequently Simulate “Pigmented Epithelioid Melanocytoma”, Expanding the Morphological Spectrum of Blue Tumors: A Clinicopathologic Study of Seven Cases. Am J Surg Pathol, doi: 10.1097/PAS.0000000000001299. [Epub ahead of print]

Ko JS., Wang L., Billings SD., Pissaloux D., Tirode F., Berry R., De La Fouchardiere A. (2019) CRTC1-TRIM11 fusion defined melanocytic tumors: A series of four cases. J Cutan Pathol. Jun 25. doi: 10.1111/cup.13533. [Epub ahead of print]

Ali N. M., Niada S., Brini A.T., Morris M. R., Kurusamy S., Alholle A., Huen D., Antonescu C.R., Tirode F., Sumathi V., Latif F. (2019) Genomic and transcriptomic characterisation of undifferentiated pleomorphic sarcoma of bone identifies recurrent alterations in chromatin remodelling genes and two previously reported gene fusions. J. Pathol. 247(2):166-176.

Ledoux P., Kind M., Le Loarer F., Stoeckle E., Italiano A., Tirode F., Buy X., Crombé A. (2019) Abnormal vascularization of soft-tissue sarcomas on conventional MRI: Diagnostic and prognostic values. Eur J Radiol. 2019 Aug;117:112-119. doi: 10.1016/j.ejrad.2019.06.007. Epub 2019 Jun 11.

Le Loarer F., Cleven AHG., Bouvier C., Castex MP., Romagosa C., Moreau A., Salas S., Bonhomme B., Gomez-Brouchet A., Laurent C., Le Guellec S., Audard V., Giraud A., Ramos-Oliver I., Cleton-Jansen AM., Savci-Heijink DC., Kroon HM., Baud J., Pissaloux D., Pierron G., Sherwood A., Coindre JM., Bovée JVMG., Larousserie F., Tirode F. (2019). A subset of epithelioid and spindle cell rhabdomyosarcomas is associated with TFCP2 fusions and common ALK upregulation. Modern Pathology. Aug 5. doi: 10.1038/s41379-019-0323-8. [Epub ahead of print].

 

2018

Brahmi, M., Alberti, L., Tirode, F., Karanian, M., Eberst, L., Cassier, P. and Blay, J.Y. (2018).Complete response to CSF1R inhibitor in a translocation variant of teno-synovial giant cell tumor without genomic alteration of the CSF1 gene. Ann Oncol. 29(6),1488-1489

Arnaud, O., Le Loarer, F. and Tirode, F., (2018). BAFfling pathologies: Alterations of BAF complexes in cancer. Cancer Letters 419, 266–279.

Watson, S., Perrin, V., Guillemot, D., Reynaud, S., Coindre, J.-M., Karanian, M., Guinebretière, J.-M., Freneaux, P., Le Loarer, F., Bouvet, M., Galmiche-Rolland, L., Larousserie, F., Longchampt, E., Ranchere-Vince, D., Pierron, G., Delattre, O. and Tirode, F. (2018) Transcriptomic definition of molecular subgroups of small round cell sarcomas. J. Pathol. 245 (1), 29-40

Alholle, A., Karanian, M., Brini, A.T., Morris, M.R., Kannappan, V., Niada, S., Niblett, A.,Ranchère-Vince, D., Pissaloux, D., Delfour, C.,Maran Gonzalez A., Antonescu, C.R. and Sumathi, V.*, Tirode, F.*, Latif, F.* (2018) Genetic analyses of undifferentiated small round cell sarcoma identifies a novel sarcoma subtype with a recurrent CRTC1-SS18 gene fusion. J Pathol. 245 (2), 186-196. *: co-last authors

Kendall, G.C., Watson, S., Xu, L., Murchison,W., Rakheja, D., Skapek, S.X.,Tirode, F., Delattre, O., Amatruda J.F. (2018). PAX3-FOXO1 transgenic zebrafish models identify HES3 as a mediator of tumorigenesis. eLife. 7, e33800. doi: 10.7554/eLife.33800.

Dadone-Montaudié, B., Alberti, L., Duc, A., Delespaul, L., Lesluyes, T., Perot, G., Lancon, A., Paindavoine, S., Di Mauro, I., Blay, J.Y., de la Fouchardière, A., Chibon, F., Karanian, M., Mac Grogan, G., Kubiniek, V., Keslair F., Cardot-Leccia, N., Michot, A., Perrin, V., Zekri, Y., Coindre, J.M., Tirode, F., Pedeutour, F., Ranchere-Vince, D., Le Loarer, F. and  Pissaloux D. (2018). Alternative PDGFD rearrangements in dermatofibrosarcomas protuberans without PDGFB fusions. Modern Pathology, 31(11):1683-1693

Pishas K. I., Drenberg C. D., Taslim C., Theisen E. R., Saund R. S., Pop I. L, Crompton B. D., Lawlor E.R, Tirode F., Mora J., Delattre O., Beckerle M. C, Callen D. F., Sharma S. & Lessnick S. L. (2018). Therapeutic targeting of KDM1A/LSD1 in Ewing sarcoma with SP-2509 engages the endoplasmic reticulum stress response. Molecular cancer Therapeutics, 17 (9), 1902-16.

Machiela, M., Grunewald, T., Surdez, D., Reynaud, S., Mirabeau, O., Karlins, E., Rubio, R., Zaidi, S., Grossetête-Lalami, S., Ballet, S., Lapouble, E., Laurence, V., Michon, J., Pierron, G., Kovar, H., Gaspar, N., Kontny, U., Gonzalez-Neira, A., Picci, P., Alonso, J., Patino-Garcia, A., Corradini, N., Marec-Bérard, P., Freedman, N., Rothman, N., Dagnall, C., Burdett, L., Jones, K., Manning, M., Wyatt, K., Zhou, W., Yeager, M., Cox, D., Hoover, R., Khan, J., Armstrong, G., Leisenring, W., Bhatia, S., Robison, L., Kulozik, A., Kriebel, J., Meitinger, T., Metzler, M., Hartmann, W., Strauch, K., Kirchner, T., Dirksen, U., Morton, L., Mirabello, L., Tucker, M., Tirode, F., Chanock, S. and Delattre, O. (2018). Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility. Nat commun, 9(1):3184.

Ignatius M. S., Hayes M. N., Moore F. E., Tang Q., Garcia S. P., Blackburn P. R., Baxi K., Wang L., Jin A., Ramakrishnan A, Reeder S., Chen Y., Nielsen G. P., Chen E. Y., Hasserjian R. P., Tirode F., Ekker S.C., Langenau, D.M. (2018). tp53 deficiency causes a wide tumor spectrum and elevates embryonal rhabdomyosarcoma metastasis in zebrafish. eLife, 7, e37202. doi: 10.7554/elife.37202.

 

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