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  1. Article ; Online: Complex Elucidation of Cells-of-Origin in Pediatric Soft Tissue Sarcoma: From Concepts to Real Life, Hide-and-Seek through Epigenetic and Transcriptional Reprogramming.

    Savary, Clara / Picard, Cécile / Corradini, Nadège / Castets, Marie

    International journal of molecular sciences

    2022  Volume 23, Issue 11

    Abstract: Soft tissue sarcoma (STS) comprise a large group of mesenchymal malignant tumors with heterogeneous cellular morphology, proliferative index, genetic lesions and, more importantly, clinical features. Full elucidation of this wide diversity remains a ... ...

    Abstract Soft tissue sarcoma (STS) comprise a large group of mesenchymal malignant tumors with heterogeneous cellular morphology, proliferative index, genetic lesions and, more importantly, clinical features. Full elucidation of this wide diversity remains a central question to improve their therapeutic management and the identity of cell(s)-of-origin from which these tumors arise is part of this enigma. Cellular reprogramming allows transitions of a mature cell between phenotypes, or identities, and represents one key driver of tumoral heterogeneity. Here, we discuss how cellular reprogramming mediated by driver genes in STS can profoundly reshape the molecular and morphological features of a transformed cell and lead to erroneous interpretation of its cell-of-origin. This review questions the fact that the epigenetic context in which a genetic alteration arises has to be taken into account as a key determinant of STS tumor initiation and progression. Retracing the cancer-initiating cell and its clonal evolution, notably via epigenetic approach, appears as a key lever for understanding the origin of these tumors and improving their clinical management.
    MeSH term(s) Cellular Reprogramming/genetics ; Epigenesis, Genetic ; Epigenomics ; Humans ; Sarcoma/genetics ; Sarcoma/therapy ; Soft Tissue Neoplasms/therapy
    Language English
    Publishing date 2022-06-04
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms23116310
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  2. Article: 99m

    Montemagno, Christopher / Cassim, Shamir / Trichanh, Dimitry / Savary, Clara / Pouyssegur, Jacques / Pagès, Gilles / Fagret, Daniel / Broisat, Alexis / Ghezzi, Catherine

    Cancers

    2019  Volume 11, Issue 10

    Abstract: Mesothelin is a membrane-associated protein overexpressed in pancreatic ductal adenocarcinoma (PDAC). Some mesothelin-targeted therapies are in clinical development but the identification of patients eligible for such therapies is still challenging. The ... ...

    Abstract Mesothelin is a membrane-associated protein overexpressed in pancreatic ductal adenocarcinoma (PDAC). Some mesothelin-targeted therapies are in clinical development but the identification of patients eligible for such therapies is still challenging. The objective of this study was to perform the imaging of mesothelin in mice models of PDAC with a technetium-labeled anti-mesothelin single-domain antibody (
    Methods: The Cancer Genomic Atlas (TCGA) database was used to determine the prognostic role of mesothelin in PDAC.
    Results: TCGA analysis showed that PDAC patients with high mesothelin expression had a shorter overall survival (P = 0.00066). The binding of
    Conclusions: 99m
    Language English
    Publishing date 2019-10-10
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2527080-1
    ISSN 2072-6694
    ISSN 2072-6694
    DOI 10.3390/cancers11101531
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  3. Article ; Online: Depicting the genetic architecture of pediatric cancers through an integrative gene network approach.

    Savary, Clara / Kim, Artem / Lespagnol, Alexandra / Gandemer, Virginie / Pellier, Isabelle / Andrieu, Charlotte / Pagès, Gilles / Galibert, Marie-Dominique / Blum, Yuna / de Tayrac, Marie

    Scientific reports

    2020  Volume 10, Issue 1, Page(s) 1224

    Abstract: The genetic etiology of childhood cancers still remains largely unknown. It is therefore essential to develop novel strategies to unravel the spectrum of pediatric cancer genes. Statistical network modeling techniques have emerged as powerful ... ...

    Abstract The genetic etiology of childhood cancers still remains largely unknown. It is therefore essential to develop novel strategies to unravel the spectrum of pediatric cancer genes. Statistical network modeling techniques have emerged as powerful methodologies for enabling the inference of gene-disease relationship and have been performed on adult but not pediatric cancers. We performed a deep multi-layer understanding of pan-cancer transcriptome data selected from the Treehouse Childhood Cancer Initiative through a co-expression network analysis. We identified six modules strongly associated with pediatric tumor histotypes that were functionally linked to developmental processes. Topological analyses highlighted that pediatric cancer predisposition genes and potential therapeutic targets were central regulators of cancer-histotype specific modules. A module was related to multiple pediatric malignancies with functions involved in DNA repair and cell cycle regulation. This canonical oncogenic module gathered most of the childhood cancer predisposition genes and clinically actionable genes. In pediatric acute leukemias, the driver genes were co-expressed in a module related to epigenetic and post-transcriptional processes, suggesting a critical role of these pathways in the progression of hematologic malignancies. This integrative pan-cancer study provides a thorough characterization of pediatric tumor-associated modules and paves the way for investigating novel candidate genes involved in childhood tumorigenesis.
    MeSH term(s) Biomarkers, Tumor/genetics ; Child ; Child, Preschool ; Computational Biology/methods ; Computer Simulation ; Databases, Genetic ; Female ; Gene Expression/genetics ; Gene Expression Profiling/methods ; Gene Expression Regulation/genetics ; Gene Expression Regulation, Neoplastic/genetics ; Gene Regulatory Networks/genetics ; Genetic Predisposition to Disease/genetics ; Genomics/methods ; Humans ; Male ; Models, Statistical ; Neoplasms/etiology ; Neoplasms/genetics ; Protein Interaction Mapping/methods ; Protein Interaction Maps/genetics ; Protein Interaction Maps/physiology ; Systems Integration ; Transcriptome/genetics
    Chemical Substances Biomarkers, Tumor
    Language English
    Publishing date 2020-01-27
    Publishing country England
    Document type Journal Article
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-020-58179-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: H3.3K27M Mutation Controls Cell Growth and Resistance to Therapies in Pediatric Glioma Cell Lines.

    Rakotomalala, Andria / Bailleul, Quentin / Savary, Clara / Arcicasa, Mélanie / Hamadou, Maud / Huchedé, Paul / Hochart, Audrey / Restouin, Audrey / Castellano, Remy / Collette, Yves / Dieny, Emma / Vincent, Audrey / Angrand, Pierre-Olivier / Le Bourhis, Xuefen / Leblond, Pierre / Furlan, Alessandro / Castets, Marie / Pasquier, Eddy / Meignan, Samuel

    Cancers

    2021  Volume 13, Issue 21

    Abstract: High-grade gliomas represent the most lethal class of pediatric tumors, and their resistance to both radio- and chemotherapy is associated with a poor prognosis. Recurrent mutations affecting histone genes drive the tumorigenesis of some pediatric high- ... ...

    Abstract High-grade gliomas represent the most lethal class of pediatric tumors, and their resistance to both radio- and chemotherapy is associated with a poor prognosis. Recurrent mutations affecting histone genes drive the tumorigenesis of some pediatric high-grade gliomas, and H3K27M mutations are notably characteristic of a subtype of gliomas called DMG (Diffuse Midline Gliomas). This dominant negative mutation impairs H3K27 trimethylation, leading to profound epigenetic modifications of genes expression. Even though this mutation was described as a driver event in tumorigenesis, its role in tumor cell resistance to treatments has not been deciphered so far. To tackle this issue, we expressed the H3.3K27M mutated histone in three initially H3K27-unmutated pediatric glioma cell lines, Res259, SF188, and KNS42. First, we validated these new H3.3K27M-expressing models at the molecular level and showed that K27M expression is associated with pleiotropic effects on the transcriptomic signature, largely dependent on cell context. We observed that the mutation triggered an increase in cell growth in Res259 and SF188 cells, associated with higher clonogenic capacities. Interestingly, we evidenced that the mutation confers an increased resistance to ionizing radiations in Res259 and KNS42 cells. Moreover, we showed that H3.3K27M mutation impacts the sensitivity of Res259 cells to specific drugs among a library of 80 anticancerous compounds. Altogether, these data highlight that, beyond its tumorigenic role, H3.3K27M mutation is strongly involved in pediatric glioma cells' resistance to therapies, likely through transcriptomic reprogramming.
    Language English
    Publishing date 2021-11-05
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2527080-1
    ISSN 2072-6694
    ISSN 2072-6694
    DOI 10.3390/cancers13215551
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  5. Article ; Online: SMAD2/3 mediate oncogenic effects of TGF-β in the absence of SMAD4.

    Bertrand-Chapel, Adrien / Caligaris, Cassandre / Fenouil, Tanguy / Savary, Clara / Aires, Sophie / Martel, Sylvie / Huchedé, Paul / Chassot, Christelle / Chauvet, Véronique / Cardot-Ruffino, Victoire / Morel, Anne-Pierre / Subtil, Fabien / Mohkam, Kayvan / Mabrut, Jean-Yves / Tonon, Laurie / Viari, Alain / Cassier, Philippe / Hervieu, Valérie / Castets, Marie /
    Mauviel, Alain / Sentis, Stéphanie / Bartholin, Laurent

    Communications biology

    2022  Volume 5, Issue 1, Page(s) 1068

    Abstract: TGF-β signaling is involved in pancreatic ductal adenocarcinoma (PDAC) tumorigenesis, representing one of the four major pathways genetically altered in 100% of PDAC cases. TGF-β exerts complex and pleiotropic effects in cancers, notably via the ... ...

    Abstract TGF-β signaling is involved in pancreatic ductal adenocarcinoma (PDAC) tumorigenesis, representing one of the four major pathways genetically altered in 100% of PDAC cases. TGF-β exerts complex and pleiotropic effects in cancers, notably via the activation of SMAD pathways, predominantly SMAD2/3/4. Though SMAD2 and 3 are rarely mutated in cancers, SMAD4 is lost in about 50% of PDAC, and the role of SMAD2/3 in a SMAD4-null context remains understudied. We herein provide evidence of a SMAD2/3 oncogenic effect in response to TGF-β1 in SMAD4-null human PDAC cancer cells. We report that inactivation of SMAD2/3 in SMAD4-negative PDAC cells compromises TGF-β-driven collective migration mediated by FAK and Rho/Rac signaling. Moreover, RNA-sequencing analyses highlight a TGF-β gene signature related to aggressiveness mediated by SMAD2/3 in the absence of SMAD4. Using a PDAC patient cohort, we reveal that SMAD4-negative tumors with high levels of phospho-SMAD2 are more aggressive and have a poorer prognosis. Thus, loss of SMAD4 tumor suppressive activity in PDAC leads to an oncogenic gain-of-function of SMAD2/3, and to the onset of associated deleterious effects.
    MeSH term(s) Carcinogenesis/genetics ; Carcinoma, Pancreatic Ductal/metabolism ; Humans ; Pancreatic Neoplasms/metabolism ; RNA ; Smad2 Protein/genetics ; Smad2 Protein/metabolism ; Smad3 Protein/metabolism ; Smad4 Protein/genetics ; Smad4 Protein/metabolism ; Transforming Growth Factor beta/pharmacology ; Transforming Growth Factor beta1/metabolism ; Pancreatic Neoplasms
    Chemical Substances SMAD2 protein, human ; SMAD3 protein, human ; SMAD4 protein, human ; Smad2 Protein ; Smad3 Protein ; Smad4 Protein ; Transforming Growth Factor beta ; Transforming Growth Factor beta1 ; RNA (63231-63-0)
    Language English
    Publishing date 2022-10-07
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2399-3642
    ISSN (online) 2399-3642
    DOI 10.1038/s42003-022-03994-6
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  6. Article ; Online: Fusion-negative rhabdomyosarcoma 3D organoids to predict effective drug combinations: A proof-of-concept on cell death inducers.

    Savary, Clara / Luciana, Léa / Huchedé, Paul / Tourbez, Arthur / Coquet, Claire / Broustal, Maëlle / Lopez Gonzalez, Alejandro / Deligne, Clémence / Diot, Thomas / Naret, Olivier / Costa, Mariana / Meynard, Nina / Barbet, Virginie / Müller, Kevin / Tonon, Laurie / Gadot, Nicolas / Degletagne, Cyril / Attignon, Valéry / Léon, Sophie /
    Vanbelle, Christophe / Bomane, Alexandra / Rochet, Isabelle / Mournetas, Virginie / Oliveira, Luciana / Rinaudo, Paul / Bergeron, Christophe / Dutour, Aurélie / Cordier-Bussat, Martine / Roch, Aline / Brandenberg, Nathalie / El Zein, Sophie / Watson, Sarah / Orbach, Daniel / Delattre, Olivier / Dijoud, Frédérique / Corradini, Nadège / Picard, Cécile / Maucort-Boulch, Delphine / Le Grand, Marion / Pasquier, Eddy / Blay, Jean-Yves / Castets, Marie / Broutier, Laura

    Cell reports. Medicine

    2023  Volume 4, Issue 12, Page(s) 101339

    Abstract: Rhabdomyosarcoma (RMS) is the main form of pediatric soft-tissue sarcoma. Its cure rate has not notably improved in the last 20 years following relapse, and the lack of reliable preclinical models has hampered the design of new therapies. This is ... ...

    Abstract Rhabdomyosarcoma (RMS) is the main form of pediatric soft-tissue sarcoma. Its cure rate has not notably improved in the last 20 years following relapse, and the lack of reliable preclinical models has hampered the design of new therapies. This is particularly true for highly heterogeneous fusion-negative RMS (FNRMS). Although methods have been proposed to establish FNRMS organoids, their efficiency remains limited to date, both in terms of derivation rate and ability to accurately mimic the original tumor. Here, we present the development of a next-generation 3D organoid model derived from relapsed adult and pediatric FNRMS. This model preserves the molecular features of the patients' tumors and is expandable for several months in 3D, reinforcing its interest to drug combination screening with longitudinal efficacy monitoring. As a proof-of-concept, we demonstrate its preclinical relevance by reevaluating the therapeutic opportunities of targeting apoptosis in FNRMS from a streamlined approach based on transcriptomic data exploitation.
    MeSH term(s) Adult ; Humans ; Child ; Neoplasm Recurrence, Local/drug therapy ; Rhabdomyosarcoma/drug therapy ; Rhabdomyosarcoma/pathology ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Organoids/pathology ; Cell Death
    Chemical Substances Antineoplastic Agents
    Language English
    Publishing date 2023-12-19
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2666-3791
    ISSN (online) 2666-3791
    DOI 10.1016/j.xcrm.2023.101339
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  7. Article ; Online: Integrated clinical and omics approach to rare diseases: novel genes and oligogenic inheritance in holoprosencephaly.

    Kim, Artem / Savary, Clara / Dubourg, Christèle / Carré, Wilfrid / Mouden, Charlotte / Hamdi-Rozé, Houda / Guyodo, Hélène / Douce, Jerome Le / Pasquier, Laurent / Flori, Elisabeth / Gonzales, Marie / Bénéteau, Claire / Boute, Odile / Attié-Bitach, Tania / Roume, Joelle / Goujon, Louise / Akloul, Linda / Odent, Sylvie / Watrin, Erwan /
    Dupé, Valérie / de Tayrac, Marie / David, Véronique

    Brain : a journal of neurology

    2018  Volume 142, Issue 1, Page(s) 35–49

    Abstract: Holoprosencephaly is a pathology of forebrain development characterized by high phenotypic heterogeneity. The disease presents with various clinical manifestations at the cerebral or facial levels. Several genes have been implicated in holoprosencephaly ... ...

    Abstract Holoprosencephaly is a pathology of forebrain development characterized by high phenotypic heterogeneity. The disease presents with various clinical manifestations at the cerebral or facial levels. Several genes have been implicated in holoprosencephaly but its genetic basis remains unclear: different transmission patterns have been described including autosomal dominant, recessive and digenic inheritance. Conventional molecular testing approaches result in a very low diagnostic yield and most cases remain unsolved. In our study, we address the possibility that genetically unsolved cases of holoprosencephaly present an oligogenic origin and result from combined inherited mutations in several genes. Twenty-six unrelated families, for whom no genetic cause of holoprosencephaly could be identified in clinical settings [whole exome sequencing and comparative genomic hybridization (CGH)-array analyses], were reanalysed under the hypothesis of oligogenic inheritance. Standard variant analysis was improved with a gene prioritization strategy based on clinical ontologies and gene co-expression networks. Clinical phenotyping and exploration of cross-species similarities were further performed on a family-by-family basis. Statistical validation was performed on 248 ancestrally similar control trios provided by the Genome of the Netherlands project and on 574 ancestrally matched controls provided by the French Exome Project. Variants of clinical interest were identified in 180 genes significantly associated with key pathways of forebrain development including sonic hedgehog (SHH) and primary cilia. Oligogenic events were observed in 10 families and involved both known and novel holoprosencephaly genes including recurrently mutated FAT1, NDST1, COL2A1 and SCUBE2. The incidence of oligogenic combinations was significantly higher in holoprosencephaly patients compared to two control populations (P < 10-9). We also show that depending on the affected genes, patients present with particular clinical features. This study reports novel disease genes and supports oligogenicity as clinically relevant model in holoprosencephaly. It also highlights key roles of SHH signalling and primary cilia in forebrain development. We hypothesize that distinction between different clinical manifestations of holoprosencephaly lies in the degree of overall functional impact on SHH signalling. Finally, we underline that integrating clinical phenotyping in genetic studies is a powerful tool to specify the clinical relevance of certain mutations.
    MeSH term(s) Case-Control Studies ; Comparative Genomic Hybridization ; Exome/genetics ; Female ; Holoprosencephaly/genetics ; Humans ; Male ; Multifactorial Inheritance/genetics ; Mutation ; Pedigree ; Phenotype ; Rare Diseases/genetics
    Language English
    Publishing date 2018-12-03
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80072-7
    ISSN 1460-2156 ; 0006-8950
    ISSN (online) 1460-2156
    ISSN 0006-8950
    DOI 10.1093/brain/awy290
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