Diversité et plasticité des tumeurs de l’enfant

Publications de l’équipe

Année de publication : 2016

Thomas G P Grünewald, Pascale Gilardi-Hebenstreit, Patrick Charnay, Olivier Delattre (2016 May 4)

[Cooperation between a somatic mutation and a genetic susceptibility variant in Ewing sarcoma].

Médecine sciences : M/S : 323-6 : DOI : 10.1051/medsci/20163204004 En savoir plus
Résumé

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Navin Pinto, Jodi R Mayfield, Gordana Raca, Mark A Applebaum, Alexandre Chlenski, Madina Sukhanova, Rochelle Bagatell, Meredith S Irwin, Anthony Little, Jawhar Rawwas, Yasmin Gosiengfiao, Olivier Delattre, Isabelle Janoueix-Lerosey, Eve Lapouble, Gudrun Schleiermacher, Susan L Cohn (2016 Feb 12)

Segmental Chromosomal Aberrations in Localized Neuroblastoma Can be Detected in Formalin-Fixed Paraffin-Embedded Tissue Samples and Are Associated With Recurrence.

Pediatric blood & cancer : 1019-23 : DOI : 10.1002/pbc.25934 En savoir plus
Résumé

Array comparative genomic hybridization (CGH) analyses of frozen tumors have shown strong associations between the pattern of chromosomal aberrations and outcome in patients with advanced-stage neuroblastoma. New platforms for analyzing chromosomal aberrations using formalin-fixed paraffin-embedded (FFPE) tissue have recently been developed. We sought to determine whether chromosomal microarray analysis (CMA) using FFPE tumors is feasible and if segmental chromosomal aberrations were prognostic of recurrence in localized neuroblastoma.

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Zhi-Yan Han, Wilfrid Richer, Paul Fréneaux, Céline Chauvin, Carlo Lucchesi, Delphine Guillemot, Camille Grison, Delphine Lequin, Gaelle Pierron, Julien Masliah-Planchon, André Nicolas, Dominique Ranchère-Vince, Pascale Varlet, Stéphanie Puget, Isabelle Janoueix-Lerosey, Olivier Ayrault, Didier Surdez, Olivier Delattre, Franck Bourdeaut (2016 Jan 29)

The occurrence of intracranial rhabdoid tumours in mice depends on temporal control of Smarcb1 inactivation.

Nature communications : 10421 : DOI : 10.1038/ncomms10421 En savoir plus
Résumé

Rhabdoid tumours (RTs) are highly aggressive tumours of infancy, frequently localized in the central nervous system (CNS) where they are termed atypical teratoid/rhabdoid tumours (AT/RTs) and characterized by bi-allelic inactivation of the SMARCB1 tumour suppressor gene. In this study, by temporal control of tamoxifen injection in Smarcb1(flox/flox);Rosa26-Cre(ERT2) mice, we explore the phenotypes associated with Smarcb1 inactivation at different developmental stages. Injection before E6, at birth or at 2 months of age recapitulates previously described phenotypes including embryonic lethality, hepatic toxicity or development of T-cell lymphomas, respectively. Injection between E6 and E10 leads to high penetrance tumours, mainly intra-cranial, with short delays (median: 3 months). These tumours demonstrate anatomical, morphological and gene expression profiles consistent with those of human AT/RTs. Moreover, intra- and inter-species comparisons of tumours reveal that human and mouse RTs can be split into different entities that may underline the variety of RT cells of origin.

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Heinrich Kovar, James Amatruda, Erika Brunet, Stefan Burdach, Florencia Cidre-Aranaz, Enrique de Alava, Uta Dirksen, Wietske van der Ent, Patrick Grohar, Thomas G P Grünewald, Lee Helman, Peter Houghton, Kristiina Iljin, Eberhard Korsching, Marc Ladanyi, Elizabeth Lawlor, Stephen Lessnick, Joseph Ludwig, Paul Meltzer, Markus Metzler, Jaume Mora, Richard Moriggl, Takuro Nakamura, Theodore Papamarkou, Branka Radic Sarikas, Francoise Rédini, Guenther H S Richter, Claudia Rossig, Keri Schadler, Beat W Schäfer, Katia Scotlandi, Nathan C Sheffield, Anang Shelat, Ewa Snaar-Jagalska, Poul Sorensen, Kimberly Stegmaier, Elizabeth Stewart, Alejandro Sweet-Cordero, Karoly Szuhai, Oscar M Tirado, Franck Tirode, Jeffrey Toretsky, Kalliopi Tsafou, Aykut Üren, Andrei Zinovyev, Olivier Delattre (2016 Jan 24)

The second European interdisciplinary Ewing sarcoma research summit – A joint effort to deconstructing the multiple layers of a complex disease.

Oncotarget : 8613-24 : DOI : 10.18632/oncotarget.6937 En savoir plus
Résumé

Despite multimodal treatment, long term outcome for patients with Ewing sarcoma is still poor. The second « European interdisciplinary Ewing sarcoma research summit » assembled a large group of scientific experts in the field to discuss their latest unpublished findings on the way to the identification of novel therapeutic targets and strategies. Ewing sarcoma is characterized by a quiet genome with presence of an EWSR1-ETS gene rearrangement as the only and defining genetic aberration. RNA-sequencing of recently described Ewing-like sarcomas with variant translocations identified them as biologically distinct diseases. Various presentations adressed mechanisms of EWS-ETS fusion protein activities with a focus on EWS-FLI1. Data were presented shedding light on the molecular underpinnings of genetic permissiveness to this disease uncovering interaction of EWS-FLI1 with recently discovered susceptibility loci. Epigenetic context as a consequence of the interaction between the oncoprotein, cell type, developmental stage, and tissue microenvironment emerged as dominant theme in the discussion of the molecular pathogenesis and inter- and intra-tumor heterogeneity of Ewing sarcoma, and the difficulty to generate animal models faithfully recapitulating the human disease. The problem of preclinical development of biologically targeted therapeutics was discussed and promising perspectives were offered from the study of novel in vitro models. Finally, it was concluded that in order to facilitate rapid pre-clinical and clinical development of novel therapies in Ewing sarcoma, the community needs a platform to maintain knowledge of unpublished results, systems and models used in drug testing and to continue the open dialogue initiated at the first two Ewing sarcoma summits.

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Année de publication : 2015

Melanie Hennchen, Jutta Stubbusch, Ikram Abarchan-El Makhfi, Marco Kramer, Thomas Deller, Cécile Pierre-Eugene, Isabelle Janoueix-Lerosey, Olivier Delattre, Uwe Ernsberger, Johannes B Schulte, Hermann Rohrer (2015 Dec 18)

Lin28B and Let-7 in the Control of Sympathetic Neurogenesis and Neuroblastoma Development.

The Journal of neuroscience : the official journal of the Society for Neuroscience : 16531-44 : DOI : 10.1523/JNEUROSCI.2560-15.2015 En savoir plus
Résumé

The RNA binding protein Lin28B is expressed in developing tissues and sustains stem and progenitor cell identity as a negative regulator of the Let-7 family of microRNAs, which induces differentiation. Lin28B is activated in neuroblastoma (NB), a childhood tumor in sympathetic ganglia and adrenal medulla. Forced expression of Lin28B in embryonic mouse sympathoadrenal neuroblasts elicits postnatal NB formation. However, the normal function of Lin28B in the development of sympathetic neurons and chromaffin cells and the mechanisms involved in Lin28B-induced tumor formation are unclear. Here, we demonstrate a mirror-image expression of Lin28B and Let-7a in developing chick sympathetic ganglia. Lin28B expression is not restricted to undifferentiated progenitor cells but, is observed in proliferating noradrenergic neuroblasts. Lin28 knockdown in cultured sympathetic neuroblasts decreases proliferation, whereas Let-7 inhibition increases the proportion of neuroblasts in the cell cycle. Lin28B overexpression enhances proliferation, but only during a short developmental period, and it does not reduce Let-7a. Effects of in vivo Lin28B overexpression were analyzed in the LSL-Lin28B(DBHiCre) mouse line. Sympathetic ganglion and adrenal medulla volume and the expression level of Let-7a were not altered, although Lin28B expression increased by 12- to 17-fold. In contrast, Let-7a expression was strongly reduced in LSL-Lin28B(DbhiCre) NB tumor tissue. These data demonstrate essential functions for endogenous Lin28 and Let-7 in neuroblast proliferation. However, Lin28B overexpression neither sustains neuroblast proliferation nor affects let-7 expression. Thus, in contrast to other pediatric tumors, Lin28B-induced NB is not due to expansion of proliferating embryonic neuroblasts, and Let-7-independent functions are implicated during initial NB development.

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Christophe Le Tourneau, Maud Kamal, Apostolia-Maria Tsimberidou, Philippe Bedard, Gaëlle Pierron, Céline Callens, Etienne Rouleau, Anne Vincent-Salomon, Nicolas Servant, Marie Alt, Roman Rouzier, Xavier Paoletti, Olivier Delattre, Ivan Bièche (2015 Nov 25)

Treatment Algorithms Based on Tumor Molecular Profiling: The Essence of Precision Medicine Trials.

Journal of the National Cancer Institute : DOI : 10.1093/jnci/djv362 En savoir plus
Résumé

With the advent of high-throughput molecular technologies, several precision medicine (PM) studies are currently ongoing that include molecular screening programs and PM clinical trials. Molecular profiling programs establish the molecular profile of patients’ tumors with the aim to guide therapy based on identified molecular alterations. The aim of prospective PM clinical trials is to assess the clinical utility of tumor molecular profiling and to determine whether treatment selection based on molecular alterations produces superior outcomes compared with unselected treatment. These trials use treatment algorithms to assign patients to specific targeted therapies based on tumor molecular alterations. These algorithms should be governed by fixed rules to ensure standardization and reproducibility. Here, we summarize key molecular, biological, and technical criteria that, in our view, should be addressed when establishing treatment algorithms based on tumor molecular profiling for PM trials.

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Julien Masliah-Planchon, Marie-Christine Machet, Paul Fréneaux, Anne Jourdain, Isabelle Mortemousque, Khadija Aït Raïs, Stelly Ballet, Anne Jouvet, Dominique Figarella-Branger, Olivier Delattre, Franck Bourdeaut (2015 Oct 16)

SMARCA4-Mutated Atypical Teratoid/Rhabdoid Tumor with Retained BRG1 Expression.

Pediatric blood & cancer : 568-9 : DOI : 10.1002/pbc.25772 En savoir plus
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Julien Calderaro, Julien Masliah-Planchon, Wilfrid Richer, Laetitia Maillot, Pascale Maille, Ludovic Mansuy, Claire Bastien, Alexandre de la Taille, Hélène Boussion, Cécile Charpy, Anne Jourdain, Claire Bléchet, Gaelle Pierron, David Gentien, Laurence Choudat, Christophe Tournigand, Olivier Delattre, Yves Allory, Franck Bourdeaut (2015 Oct 5)

Balanced Translocations Disrupting SMARCB1 Are Hallmark Recurrent Genetic Alterations in Renal Medullary Carcinomas.

European urology : DOI : S0302-2838(15)00935-5 En savoir plus
Résumé

Renal medullary carcinoma (RMC) is a rare and highly aggressive neoplasm that most often occurs in the setting of sickle cell trait or sickle cell disease (SCD). Most patients present with metastatic disease resistant to conventional chemotherapy, and therefore there is an urgent need for molecular insight to propose new therapies.

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Solveig Heide, Julien Masliah-Planchon, Bertrand Isidor, Anne Guimier, Damien Bodet, Carole Coze, Anne Deville, Estelle Thebault, Corinne Jeanne Pasquier, Elisabeth Cassagnau, Gaelle Pierron, Nathalie Clément, Gudrun Schleiermacher, Jeanne Amiel, Olivier Delattre, Michel Peuchmaur, Franck Bourdeaut (2015 Sep 17)

Oncologic Phenotype of Peripheral Neuroblastic Tumors Associated With PHOX2B Non-Polyalanine Repeat Expansion Mutations.

Pediatric blood & cancer : 71-7 : DOI : 10.1002/pbc.25723 En savoir plus
Résumé

Germline non-polyalanine repeat expansion mutations in PHOX2B (PHOX2B NPARM) predispose to peripheral neuroblastic tumors (PNT), frequently in association with other neurocristopathies: Hirschsprung disease (HSCR) or congenital central hypoventilation syndrome (CCHS). Although PHOX2B polyalanine repeat expansions predispose to a low incidence of benign PNTs, the oncologic phenotype associated with PHOX2B NPARM is still not known in detail.

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Francois Le Loarer, Sarah Watson, Gaelle Pierron, Vincent Thomas de Montpreville, Stelly Ballet, Nelly Firmin, Aurelie Auguste, Daniel Pissaloux, Sandrine Boyault, Sandrine Paindavoine, Pierre Joseph Dechelotte, Benjamin Besse, Jean Michel Vignaud, Marie Brevet, Elie Fadel, Wilfrid Richer, Isabelle Treilleux, Julien Masliah-Planchon, Mojgan Devouassoux-Shisheboran, Gerard Zalcman, Yves Allory, Franck Bourdeaut, Francoise Thivolet-Bejui, Dominique Ranchere-Vince, Nicolas Girard, Sylvie Lantuejoul, Francoise Galateau-Sallé, Jean Michel Coindre, Alexandra Leary, Olivier Delattre, Jean Yves Blay, Franck Tirode (2015 Sep 8)

SMARCA4 inactivation defines a group of undifferentiated thoracic malignancies transcriptionally related to BAF-deficient sarcomas.

Nature genetics : 1200-5 : DOI : 10.1038/ng.3399 En savoir plus
Résumé

While investigating cohorts of unclassified sarcomas by RNA sequencing, we identified 19 cases with inactivation of SMARCA4, which encodes an ATPase subunit of BAF chromatin-remodeling complexes. Clinically, the cases were all strikingly similar, presenting as compressive mediastino-pulmonary masses in 30- to 35-year-old adults with a median survival time of 7 months. To help define the nosological relationships of these tumors, we compared their transcriptomic profiles with those of SMARCA4-mutated small-cell carcinomas of the ovary, hypercalcemic type (SCCOHTs), SMARCB1-inactivated malignant rhabdoid tumors (MRTs) and lung carcinomas (of which 10% display SMARCA4 mutations). Gene profiling analyses demonstrated that these tumors were distinct from lung carcinomas but related to MRTs and SCCOHTs. Transcriptome analyses, further validated by immunohistochemistry, highlighted strong expression of SOX2, a marker that supports the differential diagnosis of these tumors from SMARCA4-deficient lung carcinomas. The prospective recruitment of cases confirmed this new category of ‘SMARCA4-deficient thoracic sarcomas’ as readily recognizable in clinical practice, providing opportunities to tailor their therapeutic management.

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Grünewald TG, Bernard V, Gilardi-Hebenstreit P, Raynal V, Surdez D, Aynaud MM, Mirabeau O, Cidre-Aranaz F, Tirode F, Zaidi S, Perot G, Jonker AH, Lucchesi C, Le Deley MC, Oberlin O, Marec-Bérard P, Véron AS, Reynaud S, Lapouble E, Boeva V, Rio Frio T, Alonso J, Bhatia S, Pierron G, Cancel-Tassin G1, Cussenot O1, Cox DG, Morton LM Machiela MJ, Chanock SJ, Charnay P, Delattre O. (2015 Sep 1)

Chimeric EWSR1-FLI1 regulates the Ewing sarcoma susceptibility gene EGR2 via a GGAA microsatellite.

Nature genetics : 47 : 1073-8 : DOI : 10.1038/ng.3363 En savoir plus
Résumé

Deciphering the ways in which somatic mutations and germline susceptibility variants cooperate to promote cancer is challenging. Ewing sarcoma is characterized by fusions between EWSR1 and members of the ETS gene family, usually EWSR1-FLI1, leading to the generation of oncogenic transcription factors that bind DNA at GGAA motifs. A recent genome-wide association study identified susceptibility variants near EGR2. Here we found that EGR2 knockdown inhibited proliferation, clonogenicity and spheroidal growth in vitro and induced regression of Ewing sarcoma xenografts. Targeted germline deep sequencing of the EGR2 locus in affected subjects and controls identified 291 Ewing-associated SNPs. At rs79965208, the A risk allele connected adjacent GGAA repeats by converting an interspaced GGAT motif into a GGAA motif, thereby increasing the number of consecutive GGAA motifs and thus the EWSR1-FLI1-dependent enhancer activity of this sequence, with epigenetic characteristics of an active regulatory element. EWSR1-FLI1 preferentially bound to the A risk allele, which increased global and allele-specific EGR2 expression. Collectively, our findings establish cooperation between a dominant oncogene and a susceptibility variant that regulates a major driver of Ewing sarcomagenesis.

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Nathalie Gaspar, Douglas S Hawkins, Uta Dirksen, Ian J Lewis, Stefano Ferrari, Marie-Cecile Le Deley, Heinrich Kovar, Robert Grimer, Jeremy Whelan, Line Claude, Olivier Delattre, Michael Paulussen, Piero Picci, Kirsten Sundby Hall, Hendrik van den Berg, Ruth Ladenstein, Jean Michon, Lars Hjorth, Ian Judson, Roberto Luksch, Mark L Bernstein, Perrine Marec-Bérard, Bernadette Brennan, Alan W Craft, Richard B Womer, Heribert Juergens, Odile Oberlin (2015 Aug 26)

Ewing Sarcoma: Current Management and Future Approaches Through Collaboration.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology : 3036-46 : DOI : 10.1200/JCO.2014.59.5256 En savoir plus
Résumé

Ewing sarcoma (ES) is an aggressive sarcoma of bone and soft tissue occurring at any age with a peak incidence in adolescents and young adults. The treatment of ES relies on a multidisciplinary approach, coupling risk-adapted intensive neoadjuvant and adjuvant chemotherapies with surgery and/or radiotherapy for control of the primary site and possible metastatic disease. The optimization of ES multimodality therapeutic strategies has resulted from the efforts of several national and international groups in Europe and North America and from cooperation between pediatric and medical oncologists. Successive first-line trials addressed the efficacy of various cyclic combinations of drugs incorporating doxorubicin, vincristine, cyclophosphamide, ifosfamide, etoposide, and dactinomycin and identified prognostic factors now used to tailor therapies. The role of high-dose chemotherapy is still debated. Current 5-year overall survival for patients with localized disease is 65% to 75%. Patients with metastases have a 5-year overall survival < 30%, except for those with isolated pulmonary metastasis (approximately 50%). Patients with recurrence have a dismal prognosis. The many insights into the biology of the EWS-FLI1 protein in the initiation and progression of ES remain to be translated into novel therapeutic strategies. Current options and future approaches will be discussed.

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Amal M El-Naggar, Chansey J Veinotte, Hongwei Cheng, Thomas G P Grunewald, Gian Luca Negri, Syam Prakash Somasekharan, Dale P Corkery, Franck Tirode, Joan Mathers, Debjit Khan, Alastair H Kyle, Jennifer H Baker, Nancy E LePard, Steven McKinney, Shamil Hajee, Momir Bosiljcic, Gabriel Leprivier, Cristina E Tognon, Andrew I Minchinton, Kevin L Bennewith, Olivier Delattre, Yuzhuo Wang, Graham Dellaire, Jason N Berman, Poul H Sorensen (2015 May 13)

Translational Activation of HIF1α by YB-1 Promotes Sarcoma Metastasis.

Cancer cell : 682-97 : DOI : 10.1016/j.ccell.2015.04.003 En savoir plus
Résumé

Metastatic dissemination is the leading cause of death in cancer patients, which is particularly evident for high-risk sarcomas such as Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma. Previous research identified a crucial role for YB-1 in the epithelial-to-mesenchymal transition (EMT) and metastasis of epithelial malignancies. Based on clinical data and two distinct animal models, we now report that YB-1 is also a major metastatic driver in high-risk sarcomas. Our data establish YB-1 as a critical regulator of hypoxia-inducible factor 1α (HIF1α) expression in sarcoma cells. YB-1 enhances HIF1α protein expression by directly binding to and activating translation of HIF1A messages. This leads to HIF1α-mediated sarcoma cell invasion and enhanced metastatic capacity in vivo, highlighting a translationally regulated YB-1-HIF1α axis in sarcoma metastasis.

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Irina Lambertz, Candy Kumps, Shana Claeys, Sven Lindner, Anneleen Beckers, Els Janssens, Daniel R Carter, Alex Cazes, Belamy B Cheung, Marilena De Mariano, An De Bondt, Sara De Brouwer, Olivier Delattre, Jay Gibbons, Isabelle Janoueix-Lerosey, Geneviève Laureys, Chris Liang, Glenn M Marchall, Michael Porcu, Junko Takita, David Camacho Trujillo, Ilse Van Den Wyngaert, Nadine Van Roy, Alan Van Goethem, Tom Van Maerken, Piotr Zabrocki, Jan Cools, Johannes H Schulte, Jorge Vialard, Frank Speleman, Katleen De Preter (2015 Mar 26)

Upregulation of MAPK Negative Feedback Regulators and RET in Mutant ALK Neuroblastoma: Implications for Targeted Treatment.

Clinical cancer research : an official journal of the American Association for Cancer Research : 3327-39 : DOI : 10.1158/1078-0432.CCR-14-2024 En savoir plus
Résumé

Activating ALK mutations are present in almost 10% of primary neuroblastomas and mark patients for treatment with small-molecule ALK inhibitors in clinical trials. However, recent studies have shown that multiple mechanisms drive resistance to these molecular therapies. We anticipated that detailed mapping of the oncogenic ALK-driven signaling in neuroblastoma can aid to identify potential fragile nodes as additional targets for combination therapies.

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Syam Prakash Somasekharan, Amal El-Naggar, Gabriel Leprivier, Hongwei Cheng, Shamil Hajee, Thomas G P Grunewald, Fan Zhang, Tony Ng, Olivier Delattre, Valentina Evdokimova, Yuzhuo Wang, Martin Gleave, Poul H Sorensen (2015 Mar 25)

YB-1 regulates stress granule formation and tumor progression by translationally activating G3BP1.

The Journal of cell biology : 913-29 : DOI : 10.1083/jcb.201411047 En savoir plus
Résumé

Under cell stress, global protein synthesis is inhibited to preserve energy. One mechanism is to sequester and silence mRNAs in ribonucleoprotein complexes known as stress granules (SGs), which contain translationally silent mRNAs, preinitiation factors, and RNA-binding proteins. Y-box binding protein 1 (YB-1) localizes to SGs, but its role in SG biology is unknown. We now report that YB-1 directly binds to and translationally activates the 5′ untranslated region (UTR) of G3BP1 mRNAs, thereby controlling the availability of the G3BP1 SG nucleator for SG assembly. YB-1 inactivation in human sarcoma cells dramatically reduces G3BP1 and SG formation in vitro. YB-1 and G3BP1 expression are highly correlated in human sarcomas, and elevated G3BP1 expression correlates with poor survival. Finally, G3BP1 down-regulation in sarcoma xenografts prevents in vivo SG formation and tumor invasion, and completely blocks lung metastasis in mouse models. Together, these findings demonstrate a critical role for YB-1 in SG formation through translational activation of G3BP1, and highlight novel functions for SGs in tumor progression.

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