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1. CNS tumors with PLAGL1-fusion: beyond ZFTA and YAP1 in the genetic spectrum of supratentorial ependymomas

Author

Arnault Tauziède-Espariat, Yvan Nicaise, Philipp Sievers, Felix Sahm, Andreas von Deimling, Delphine Guillemot, Gaëlle Pierron, Mathilde Duchesne, Myriam Edjlali, Volodia Dangouloff-Ros, Nathalie Boddaert, Alexandre Roux, Edouard Dezamis, Lauren Hasty, Benoît Lhermitte, Edouard Hirsch, Maria Paola Valenti Hirsch, François-Daniel Ardellier, Mélodie-Anne Karnoub, Marie Csanyi, Claude-Alain Maurage, Karima Mokhtari, Franck Bielle, Valérie Rigau, Thomas Roujeau, Marine Abad, Sébastien Klein, Michèle Bernier, Catherine Horodyckid, Clovis Adam, Petter Brandal, Pitt Niehusmann, Quentin Vannod-Michel, Corentin Provost, Nicolas Menjot de Champfleur, Lucia Nichelli, Alice Métais, Cassandra Mariet, Fabrice Chrétien, Thomas Blauwblomme, Kévin Beccaria, Johan Pallud, Stéphanie Puget, Emmanuelle Uro-Coste, Pascale Varlet, and RENOCLIP-LOC

Subjects
Ependymoma, PLAGL1, Subependymoma, DNA-methylation, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract A novel methylation class, “neuroepithelial tumor, with PLAGL1 fusion” (NET-PLAGL1), has recently been described, based on epigenetic features, as a supratentorial pediatric brain tumor with recurrent histopathological features suggesting an ependymal differentiation. Because of the recent identification of this neoplastic entity, few histopathological, radiological and clinical data are available. Herein, we present a detailed series of nine cases of PLAGL1-fused supratentorial tumors, reclassified from a series of supratentorial ependymomas, non-ZFTA/non-YAP1 fusion-positive and subependymomas of the young. This study included extensive clinical, radiological, histopathological, ultrastructural, immunohistochemical, genetic and epigenetic (DNA methylation profiling) data for characterization. An important aim of this work was to evaluate the sensitivity and specificity of a novel fluorescent in situ hybridization (FISH) targeting the PLAGL1 gene. Using histopathology, immunohistochemistry and electron microscopy, we confirmed the ependymal differentiation of this new neoplastic entity. Indeed, the cases histopathologically presented as “mixed subependymomas-ependymomas” with well-circumscribed tumors exhibiting a diffuse immunoreactivity for GFAP, without expression of Olig2 or SOX10. Ultrastructurally, they also harbored features reminiscent of ependymal differentiation, such as cilia. Different gene partners were fused with PLAGL1: FOXO1, EWSR1 and for the first time MAML2. The PLAGL1 FISH presented a 100% sensitivity and specificity according to RNA sequencing and DNA methylation profiling results. This cohort of supratentorial PLAGL1-fused tumors highlights: 1/ the ependymal cell origin of this new neoplastic entity; 2/ benefit of looking for a PLAGL1 fusion in supratentorial cases of non-ZFTA/non-YAP1 ependymomas; and 3/ the usefulness of PLAGL1 FISH.

Published
2024
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3. CNS tumor with EP300::BCOR fusion: discussing its prevalence in adult population

Author

Arnault Tauziède-Espariat, Emmanuelle Uro-Coste, Philipp Sievers, Yvan Nicaise, Cassandra Mariet, Aurore Siegfried, Gaëlle Pierron, Delphine Guillemot, Joseph Benzakoun, Johan Pallud, Margaux Roques, Fabrice Bonneville, Delphine Larrieu-Ciron, Patrick Chaynes, Raphaël Saffroy, Jocelyne Hamelin, Lauren Hasty, Alice Métais, Fabrice Chrétien, Marcel Kool, Johannes Gojo, Pascale Varlet, and RENOCLIP-LOC

Subjects
EP300, BCOR, Adult, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract The Central Nervous System (CNS) tumor with BCOR internal tandem duplication (ITD) has recently been added as a novel embryonal histomolecular tumor type to the 2021 World Health Organization (WHO) Classification of CNS Tumors. In addition, other CNS tumors harboring a BCOR/BCORL1 fusion, which are defined by a distinct DNA-methylation profile, have been recently identified in the literature but clinical, radiological and histopathological data remain scarce. Herein, we present two adult cases of CNS tumors with EP300::BCOR fusion. These two cases presented radiological, histopathological, and immunohistochemical homologies with CNS tumors having BCOR ITD in children. To compare these tumors with different BCOR alterations, we performed a literature review with a meta-analysis. CNS tumors with EP300::BCOR fusion seem to be distinct from their BCOR ITD counterparts in terms of age, location, progression-free survival, tumor growth pattern, and immunopositivity for the BCOR protein. CNS tumors from the EP300::BCOR fusion methylation class in adults may be added to the future WHO classification.

Published
2023
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4. Disseminated diffuse midline gliomas, H3K27-altered mimicking diffuse leptomeningeal glioneuronal tumors: a diagnostical challenge!

Author

Arnault Tauziède-Espariat, Aurore Siegfried, Emmanuelle Uro-Coste, Yvan Nicaise, David Castel, Annick Sevely, Marion Gambart, Sergio Boetto, Lauren Hasty, Alice Métais, Fabrice Chrétien, Joseph Benzakoun, Stéphanie Puget, Jacques Grill, Volodia Dangouloff-Ros, Nathalie Boddaert, Azadeh Ebrahimi, Pascale Varlet, and the RENOCLIP-LOC Network

Subjects
Neurology. Diseases of the nervous system, RC346-429
Published
2022
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5. Overexpression of Growth Differentiation Factor 15 in Glioblastoma Stem Cells Promotes Their Radioresistance

Author

Alexandre Bentaberry-Rosa, Yvan Nicaise, Caroline Delmas, Valérie Gouazé-Andersson, Elizabeth Cohen-Jonathan-Moyal, and Catherine Seva

Subjects
glioblastomas, radioresistance, signaling, GDF15, cancer stem cells, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

GSCs play an important role in GBM recurrence. Understanding the resistance mechanisms in these cells is therefore crucial for radiation therapy optimization. In this study, using patient-derived GSCs, we demonstrate that GDF15, a cytokine belonging to the TGF-β superfamily, is regulated by irradiation (IR) and the transcription factor WWTR1/TAZ. Blocking WWTR1/TAZ using specific siRNAs significantly reduces GDF15 basal expression and reverses the upregulation of this cytokine induced by IR. Furthermore, we demonstrate that GDF15 plays an important role in GSC radioresistance. Targeting GDF15 expression by siRNA in GSCs expressing high levels of GDF15 sensitizes the cells to IR. In addition, we also found that GDF15 expression is critical for GSC spheroid formation, as GDF15 knockdown significantly reduces the number of GSC neurospheres. This study suggests that GDF15 targeting in combination with radiotherapy may be a feasible approach in patients with GBM.

Published
2023
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6. Supratentorial non-RELA, ZFTA-fused ependymomas: a comprehensive phenotype genotype correlation highlighting the number of zinc fingers in ZFTA-NCOA1/2 fusions

Author

Arnault Tauziède-Espariat, Aurore Siegfried, Yvan Nicaise, Thomas Kergrohen, Philipp Sievers, Alexandre Vasiljevic, Alexandre Roux, Edouard Dezamis, Chiara Benevello, Marie-Christine Machet, Sophie Michalak, Chloe Puiseux, Francisco Llamas-Gutierrez, Pierre Leblond, Franck Bourdeaut, Jacques Grill, Christelle Dufour, Léa Guerrini-Rousseau, Samuel Abbou, Volodia Dangouloff-Ros, Nathalie Boddaert, Raphaël Saffroy, Lauren Hasty, Ellen Wahler, Mélanie Pagès, Felipe Andreiuolo, Emmanuèle Lechapt, Fabrice Chrétien, Thomas Blauwblomme, Kévin Beccaria, Johan Pallud, Stéphanie Puget, Emmanuelle Uro-Coste, Pascale Varlet, and the RENOCLIP-LOC, the BIOMECA (Biomarkers for Ependymomas in Children, Adolescents) consortium

Subjects
Ependymoma, ZFTA, RELA, DNA-methylation, Clusters, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract The cIMPACT-NOW Update 7 has replaced the WHO nosology of “ependymoma, RELA fusion positive” by “Supratentorial-ependymoma, C11orf95-fusion positive”. This modification reinforces the idea that supratentorial-ependymomas exhibiting fusion that implicates the C11orf95 (now called ZFTA) gene with or without the RELA gene, represent the same histomolecular entity. A hot off the press molecular study has identified distinct clusters of the DNA methylation class of ZFTA fusion-positive tumors. Interestingly, clusters 2 and 4 comprised tumors of different morphologies, with various ZFTA fusions without involvement of RELA. In this paper, we present a detailed series of thirteen cases of non-RELA ZFTA-fused supratentorial tumors with extensive clinical, radiological, histopathological, immunohistochemical, genetic and epigenetic (DNA methylation profiling) characterization. Contrary to the age of onset and MRI aspects similar to RELA fusion-positive EPN, we noted significant histopathological heterogeneity (pleomorphic xanthoastrocytoma-like, astroblastoma-like, ependymoma-like, and even sarcoma-like patterns) in this cohort. Immunophenotypically, these NFκB immunonegative tumors expressed GFAP variably, but EMA constantly and L1CAM frequently. Different gene partners were fused with ZFTA: NCOA1/2, MAML2 and for the first time MN1. These tumors had epigenetic homologies within the DNA methylation class of ependymomas-RELA and were classified as satellite clusters 2 and 4. Cluster 2 (n = 9) corresponded to tumors with classic ependymal histological features (n = 4) but also had astroblastic features (n = 5). Various types of ZFTA fusions were associated with cluster 2, but as in the original report, ZFTA:MAML2 fusion was frequent. Cluster 4 was enriched with sarcoma-like tumors. Moreover, we reported a novel anatomy of three ZFTA:NCOA1/2 fusions with only 1 ZFTA zinc finger domain in the putative fusion protein, whereas all previously reported non-RELA ZFTA fusions have 4 ZFTA zinc fingers. All three cases presented a sarcoma-like morphology. This genotype/phenotype association requires further studies for confirmation. Our series is the first to extensively characterize this new subset of supratentorial ZFTA-fused ependymomas and highlights the usefulness of ZFTA FISH analysis to confirm the existence of a rearrangement without RELA abnormality.

Published
2021
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7. The EP300:BCOR fusion extends the genetic alteration spectrum defining the new tumoral entity of 'CNS tumors with BCOR internal tandem duplication'

Author

Arnault Tauziède-Espariat, Gaëlle Pierron, Aurore Siegfried, Delphine Guillemot, Emmanuelle Uro-Coste, Yvan Nicaise, David Castel, Isabelle Catalaa, Delphine Larrieu-Ciron, Patrick Chaynes, Amaury de Barros, Julien Nicolau, Albane Gareton, Emmanuèle Lechapt, Fabrice Chrétien, Franck Bourdeaut, François Doz, Yassine Bouchoucha, Jacques Grill, Kévin Beccaria, Nathalie Boddaert, Raphaël Saffroy, Mélanie Pagès, and Pascale Varlet

Subjects
Neurology. Diseases of the nervous system, RC346-429
Published
2020
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8. Pediatric methylation class HGNET-MN1: unresolved issues with terminology and grading

Author

Arnault Tauziède-Espariat, Mélanie Pagès, Alexandre Roux, Aurore Siegfried, Emmanuelle Uro-Coste, Yvan Nicaise, Annick Sevely, Marion Gambart, Sergio Boetto, Martin Dupuy, Pomone Richard, Romain Perbet, Matthieu Vinchon, Sabine Caron, Felipe Andreiuolo, Albane Gareton, Emmanuèle Lechapt, Fabrice Chrétien, Stéphanie Puget, Jacques Grill, Nathalie Boddaert, Pascale Varlet, and on behalf of the RENOCLIP-LOC

Subjects
MN1, HGNET, Astroblastoma, Meta-analysis, Neurology. Diseases of the nervous system, RC346-429
Published
2019
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9. The Glycoprotein M6a Is Associated with Invasiveness and Radioresistance of Glioblastoma Stem Cells

Author

Marie Geraldine Lacore, Caroline Delmas, Yvan Nicaise, Aline Kowalski-Chauvel, Elizabeth Cohen-Jonathan-Moyal, and Catherine Seva

Subjects
glioblastomas, invasion, radioresistance, cancer stem cells, GPM6A, PTPRZ1, Cytology, QH573-671
Abstract

Systematic recurrence of glioblastoma (GB) despite surgery and chemo-radiotherapy is due to GB stem cells (GBSC), which are particularly invasive and radioresistant. Therefore, there is a need to identify new factors that might be targeted to decrease GBSC invasive capabilities as well as radioresistance. Patient-derived GBSC were used in this study to demonstrate a higher expression of the glycoprotein M6a (GPM6A) in invasive GBSC compared to non-invasive cells. In 3D invasion assays performed on primary neurospheres of GBSC, we showed that blocking GPM6A expression by siRNA significantly reduced cell invasion. We also demonstrated a high correlation of GPM6A with the oncogenic protein tyrosine phosphatase, PTPRZ1, which regulates GPM6A expression and cell invasion. The results of our study also show that GPM6A and PTPRZ1 are crucial for GBSC sphere formation. Finally, we demonstrated that targeting GPM6A or PTPRZ1 in GBSC increases the radiosensitivity of GBSC. Our results suggest that blocking GPM6A or PTPRZ1 could represent an interesting approach in the treatment of glioblastoma since it would simultaneously target proliferation, invasion, and radioresistance.

Published
2022
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10. Brain tumor with an ATXN1-NUTM1 fusion gene expands the histologic spectrum of NUTM1-rearranged neoplasia

Author

Aurore Siegfried, Julien Masliah-Planchon, Franck-Emmanuel Roux, Delphine Larrieu-Ciron, Gaelle Pierron, Yvan Nicaise, Marion Gambart, Isabelle Catalaa, Sarah Péricart, Charlotte Dubucs, Badreddine Mohand-Oumoussa, Franck Tirode, Franck Bourdeaut, and Emmanuelle Uro-Coste

Subjects
NUTM1, ATXN1, NUTM1-rearranged neoplasia, RNA sequencing, DNA methylation-based classification, Central nervous system, Neurology. Diseases of the nervous system, RC346-429
Published
2019
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11. Neuronal sphingosine kinase 2 subcellular localization is altered in Alzheimer’s disease brain

Author

Gaëlle Dominguez, Marie-Lise Maddelein, Mélanie Pucelle, Yvan Nicaise, Claude-Alain Maurage, Charles Duyckaerts, Olivier Cuvillier, and Marie-Bernadette Delisle

Subjects
Alzheimer’s disease, Neuropathology, β-amyloid, Sphingolipids, Sphingosine kinase 2, Sphingosine 1-phosphate, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background Alzheimer’s disease (AD) is characterized by the accumulation of β-amyloid (Aβ) peptides and hyperphosphorylated tau protein accompanied by neuronal loss. Aβ accumulation has been associated with an impaired sphingosine 1-phosphate (S1P) metabolism. S1P is generated by sphingosine kinases (SphKs), of which there are two isoenzymes SphK1 and SphK2, and degraded by the sphingosine 1-phosphate lyase (SPL). We previously reported, that both a decrease in SphK1 expression and an increase in SPL expression, correlated with amyloid deposits in the entorhinal cortex of AD brains, suggesting a global loss of pro-survival S1P in AD neurons. SphK2 contribution has also been examined in AD yielding to conflicting results that may reflect the complexity of SphK2 regulation. The subcellular localization of SphK2, hence the compartmentalization of generated S1P, is recognized to play a crucial role in dictating either its pro-survival or pro-apoptotic functions. We therefore aimed at studying the expression of SphK2 and notably its subcellular localization in brain tissues from patients with AD. Results We report that a decrease in SphK2 protein cytosolic expression correlated with the density of amyloid deposits in a cohort of 25 post-mortem brains. Interestingly, we observed that the equilibrium between cytoplasmic and nuclear SphK2 is disrupted and showed that SphK2 is preferentially localized in the nucleus in AD brain extracts as compared to control extracts, with a marked increase of cleaved SphK2. Conclusions Our results suggest that a shift in the subcellular localization of the S1P generating SphK2 may compromise the well established pro-survival cytosolic S1P by favoring the production of nuclear S1P associated with adverse effects in AD pathogenesis.

Published
2018
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12. The STEMRI trial: magnetic resonance spectroscopy imaging can define tumor areas enriched in glioblastoma-initiating cells

Author

Anthony Lemarié, Vincent Lubrano, Caroline Delmas, Amélie Lusque, Juan-Pablo Cerapio, Marion Perrier, Aurore Siegfried, Florent Arnauduc, Yvan Nicaise, Perrine Dahan, Thomas Filleron, Muriel Mounier, Christine Toulas, and Elizabeth Cohen-Jonathan Moyal

Abstract

BACKGROUNDGlioblastoma (GB) gold standard treatment combines maximally-safe surgical resection of the contrast-enhanced (CE) central tumor area, as defined by MRI, and chemo-radiotherapy. However, most patients relapse within one year in non-CE peritumoral FLAIR regions. Spectroscopy MRI (MRSI) can discriminate metabolic tumor areas with higher recurrence potential. We showed that regions with Choline/N-acetyl-aspartate index >2 (CNI+) were predictive of relapse sites post-radiotherapy in CE and FLAIR areas. As relapses are mainly imputed to a subpopulation of aggressive and resistant tumor stem-like cells, called GB-initiating cells (GIC), this suggests that CNI+ areas might be enriched in GIC.METHODSWe conducted a prospective trial in 16 eligible GB patients subjected to preoperative MRSI/MRI and subsequent surgery/chemo-radiotherapy to investigate GIC enrichment of CNI+ versus CNI− areas, based on biopsies in CE and FLAIR. We combined in vitro/vivo biological characterization of biopsies and derived GIC lines with biopsy RNAseq analyses.RESULTSBiopsy characterization by FACS and RNAseq revealed that FLAIR/CNI+ areas showed an enrichment in GIC-population and in stem-related gene signature, but also in pathways related to DNA repair, adhesion/migration and mitochondrial bioenergetics. More, FLAIR/CNI+ samples gave rise to GIC-enriched neurospheres faster than CNI− counterparts. Finally, parameters assessing Biopsy GIC Content and Time to Neurosphere formation in FLAIR/CNI+ areas were associated with worse patient outcome.CONCLUSIONPreoperative MRI/MRSI combination would certainly allow better resection and targeting of CNI+ areas in FLAIR, as their GIC-enrichment can predict worse outcome in GB patients.TRIAL REGISTRATIONClinicalTrials.govNCT01872221.FUNDINGRITC (RECF1929), GRICR and Plan Cancer 2016 (HTE).

Published
2023

13. A novel YAP1-MAML2 fusion in an adult supra-tentorial ependymoma, YAP1-fused

Author

Arnault, Tauziède-Espariat, Aurore, Siegfried, Yvan, Nicaise, Dominique, Figarella-Branger, Romain, Appay, Suhan, Senova, Dorian, Bochaton, Lauren, Hasty, Anna, Martin, Fabrice, Chrétien, Alice, Métais, Pascale, Varlet, Emmanuelle, Uro-Coste, Institut de neurophysiopathologie (INP), and Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Adult, MESH: YAP-Signaling Proteins, MESH: Humans, MESH: Trans-Activators, [SDV]Life Sciences [q-bio], Supratentorial Neoplasms, YAP-Signaling Proteins, MESH: Adult, MESH: Ependymoma, MESH: Transcription Factors, MESH: Supratentorial Neoplasms, Ependymoma, MESH: Gene Fusion, Trans-Activators, Humans, Gene Fusion, Transcription Factors
Published
2022

14. Clinicopathological and molecular characterization of three cases classified by DNA-methylation profiling as 'Glioneuronal Tumors, NOS, Subtype A'

Author

Arnault, Tauziède-Espariat, Volodia-Dangouloff-Ros, Dominique, Figarella-Branger, Emmanuelle, Uro-Coste, Yvan, Nicaise, Nicolas, André, Didier, Scavarda, Benoît, Testud, Nadine, Girard, Audrey, Rousseau, Laetitia, Basset, Guillaume, Chotard, Vincent, Jecko, François, le Loarer, Isabelle, Hostein, Marie-Christine, Machet, Matthias, Tallegas, Antoine, Listrat, Lauren, Hasty, Alice, Métais, Fabrice, Chrétien, Nathalie, Boddaert, and Pascale, Varlet

Subjects
Central Nervous System Neoplasms, Brain Neoplasms, Humans, DNA, DNA Methylation, Methylation, Neoplasms, Neuroepithelial
Published
2022

15. The EP300:BCOR fusion extends the genetic alteration spectrum defining the new tumoral entity of 'CNS tumors with BCOR internal tandem duplication'

Author

Nathalie Boddaert, Fabrice Chrétien, Raphaël Saffroy, Gaëlle Pierron, Yvan Nicaise, Amaury De Barros, Emmanuelle Uro-Coste, Delphine Larrieu-Ciron, David Castel, Julien Nicolau, Yassine Bouchoucha, Kevin Beccaria, Arnault Tauziède-Espariat, I. Catalaa, Patrick Chaynes, Jacques Grill, Emmanuèle Lechapt, Albane Gareton, Aurore Siegfried, Pascale Varlet, François Doz, Mélanie Pagès, Franck Bourdeaut, and Delphine Guillemot

Subjects
business.industry, Genetic Alteration, Internal tandem duplication, Computational biology, Biology, lcsh:RC346-429, Pathology and Forensic Medicine, Cellular and Molecular Neuroscience, Text mining, Neurology (clinical), CNS TUMORS, EP300, business, Letter to the Editor, lcsh:Neurology. Diseases of the nervous system
Published
2020

17. Supratentorial non-RELA, ZFTA-fused ependymomas: a comprehensive phenotype genotype correlation highlighting the number of zinc fingers in ZFTA-NCOA1/2 fusions

Author

Mélanie Pagès, Samuel Abbou, Emmanuelle Uro-Coste, Philipp Sievers, Fabrice Chrétien, Kevin Beccaria, Francisco Llamas-Gutierrez, Chloe Puiseux, Volodia Dangouloff-Ros, Léa Guerrini-Rousseau, Chiara Benevello, Yvan Nicaise, Marie-Christine Machet, Ellen Wahler, Nathalie Boddaert, Felipe Andreiuolo, Stéphanie Puget, Christelle Dufour, Sophie Michalak, Thomas Blauwblomme, Emmanuèle Lechapt, Alexandre Vasiljevic, Pierre Leblond, Arnault Tauziède-Espariat, Edouard Dezamis, Alexandre Roux, Raphaël Saffroy, Aurore Siegfried, Johan Pallud, Pascale Varlet, Franck Bourdeaut, Lauren Hasty, Thomas Kergrohen, and Jacques Grill

Subjects
Ependymoma, Adult, Male, Pathology, medicine.medical_specialty, Adolescent, Genotype, Neural Cell Adhesion Molecule L1, RELA, Biology, Pathology and Forensic Medicine, Clusters, Cellular and Molecular Neuroscience, Nuclear Receptor Coactivator 2, Young Adult, Nuclear Receptor Coactivator 1, Glial Fibrillary Acidic Protein, medicine, Humans, ZFTA, Epigenetics, RC346-429, Child, Gene, Zinc finger, Tumor Suppressor Proteins, Research, NF-kappa B, Transcription Factor RelA, Infant, Proteins, Supratentorial Neoplasms, DNA Methylation, medicine.disease, Fusion protein, Phenotype, Child, Preschool, DNA methylation, Trans-Activators, Female, Neurology (clinical), Neurology. Diseases of the nervous system, Gene Fusion, DNA-methylation
Abstract

The cIMPACT-NOW Update 7 has replaced the WHO nosology of “ependymoma, RELA fusion positive” by “Supratentorial-ependymoma, C11orf95-fusion positive”. This modification reinforces the idea that supratentorial-ependymomas exhibiting fusion that implicates the C11orf95 (now called ZFTA) gene with or without the RELA gene, represent the same histomolecular entity. A hot off the press molecular study has identified distinct clusters of the DNA methylation class of ZFTA fusion-positive tumors. Interestingly, clusters 2 and 4 comprised tumors of different morphologies, with various ZFTA fusions without involvement of RELA. In this paper, we present a detailed series of thirteen cases of non-RELA ZFTA-fused supratentorial tumors with extensive clinical, radiological, histopathological, immunohistochemical, genetic and epigenetic (DNA methylation profiling) characterization. Contrary to the age of onset and MRI aspects similar to RELA fusion-positive EPN, we noted significant histopathological heterogeneity (pleomorphic xanthoastrocytoma-like, astroblastoma-like, ependymoma-like, and even sarcoma-like patterns) in this cohort. Immunophenotypically, these NFκB immunonegative tumors expressed GFAP variably, but EMA constantly and L1CAM frequently. Different gene partners were fused with ZFTA: NCOA1/2, MAML2 and for the first time MN1. These tumors had epigenetic homologies within the DNA methylation class of ependymomas-RELA and were classified as satellite clusters 2 and 4. Cluster 2 (n = 9) corresponded to tumors with classic ependymal histological features (n = 4) but also had astroblastic features (n = 5). Various types of ZFTA fusions were associated with cluster 2, but as in the original report, ZFTA:MAML2 fusion was frequent. Cluster 4 was enriched with sarcoma-like tumors. Moreover, we reported a novel anatomy of three ZFTA:NCOA1/2 fusions with only 1 ZFTA zinc finger domain in the putative fusion protein, whereas all previously reported non-RELA ZFTA fusions have 4 ZFTA zinc fingers. All three cases presented a sarcoma-like morphology. This genotype/phenotype association requires further studies for confirmation. Our series is the first to extensively characterize this new subset of supratentorial ZFTA-fused ependymomas and highlights the usefulness of ZFTA FISH analysis to confirm the existence of a rearrangement without RELA abnormality.

Published
2021

18. Brain tumor with an ATXN1-NUTM1 fusion gene expands the histologic spectrum of NUTM1-rearranged neoplasia

Author

Charlotte Dubucs, Aurore Siegfried, Emmanuelle Uro-Coste, Gaëlle Pierron, I. Catalaa, Marion Gambart, Julien Masliah-Planchon, Badreddine Mohand-Oumoussa, Franck Tirode, Sarah Péricart, Franck Bourdeaut, Franck-Emmanuel Roux, Delphine Larrieu-Ciron, Yvan Nicaise, Département de Pathologie [CHU Toulouse], CHU Toulouse [Toulouse], Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Génétique Somatique, Institut Curie, Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de Recherche en Cancérologie de Lyon (CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), TIRODE, Franck, Service Anatomie et cytologie pathologiques [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), and Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)

Subjects
medicine.medical_specialty, Pathology, Neurology, CIC-ATXN1-ATXN1L axis, DNA methylation-based classification, Central nervous system, Brain tumor, Oncogenic gene fusions, CIC-ATXN1-ATXN1L axis, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, lcsh:RC346-429, Pathology and Forensic Medicine, Fusion gene, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], ATXN1, medicine, Letter to the Editor, lcsh:Neurology. Diseases of the nervous system, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, NUTM1-rearranged neoplasia, RNA sequencing, NUTM1, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Oncogenic gene fusions, medicine.anatomical_structure, 030220 oncology & carcinogenesis, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Neurology (clinical)
Abstract

International audience

Published
2019

19. Pediatric methylation class HGNET-MN1: unresolved issues with terminology and grading

Author

Pascale Varlet, Fabrice Chrétien, Stéphanie Puget, Sergio Boetto, Arnault Tauziède-Espariat, Felipe Andreiuolo, Matthieu Vinchon, Marion Gambart, J. Grill, Pomone Richard, Annick Sevely, Mélanie Pagès, Emmanuèle Lechapt, Romain Perbet, Yvan Nicaise, Martin Dupuy, Sabine Caron, Nathalie Boddaert, Aurore Siegfried, Albane Gareton, Emmanuelle Uro-Coste, and Alexandre Roux

Subjects
medicine.medical_specialty, Astroblastoma, lcsh:RC346-429, Pathology and Forensic Medicine, Terminology, Cellular and Molecular Neuroscience, medicine, Humans, Medical physics, Grading (tumors), Letter to the Editor, lcsh:Neurology. Diseases of the nervous system, MN1, business.industry, Brain Neoplasms, Tumor Suppressor Proteins, medicine.disease, Neoplasms, Neuroepithelial, Meta-analysis, HGNET, Trans-Activators, Neurology (clinical), Neoplasm Grading, business, Follow-Up Studies
Published
2019

20. Ionizing radiation induces endothelial transdifferentiation of glioblastoma stem-like cells through the Tie2 signaling pathway

Author

Pauline Deshors, Christine Toulas, Florent Arnauduc, Laure Malric, Aurore Siegfried, Yvan Nicaise, Anthony Lemarié, Dorian Larrieu, Marie Tosolini, Elizabeth Cohen-Jonathan Moyal, Monique Courtade-Saidi, and Solène M. Evrard

Subjects
Neoplasms, Radiation-Induced, Radiotherapy, Neovascularization, Pathologic, lcsh:Cytology, Cancer stem cells, Endothelial Cells, Receptor, TIE-2, Xenograft Model Antitumor Assays, Article, CNS cancer, Mice, Cell Line, Tumor, Radiation, Ionizing, embryonic structures, Cell Transdifferentiation, cardiovascular system, Neoplastic Stem Cells, Animals, Blood Vessels, Humans, lcsh:QH573-671, Neoplasm Recurrence, Local, Glioblastoma, Cell Proliferation, Signal Transduction
Abstract

Glioblastomas (GBM) are brain tumors with a poor prognosis despite treatment that combines surgical resection and radio-chemotherapy. These tumors are characterized by abundant vascularization and significant cellular heterogeneity including GBM stem-like cells (GSC) which contribute to tumor aggressiveness, resistance, and recurrence. Recent data has demonstrated that GSC are directly involved in the formation of new vessels via their transdifferentiation into Tumor Derived Endothelial Cells (TDEC). We postulate that cellular stress such as ionizing radiation (IR) could enhance the transdifferentiation of GSC into TDEC. GSC neurospheres isolated from 3 different patients were irradiated or not and were then transdifferentiated into TDEC. In fact, TDEC obtained from irradiated GSC (TDEC IR+) migrate more towards VEGF, form more pseudotubes in MatrigelTM in vitro and develop more functional blood vessels in MatrigelTM plugs implanted in Nude mice than TDEC obtained from non-irradiated GSC. Transcriptomic analysis allows us to highlight an overexpression of Tie2 in TDEC IR+. All IR-induced effects on TDEC were abolished by using a Tie2 kinase inhibitor, which confirms the role of the Tie2 signaling pathway in this process. Finally, by analyzing Tie2 expression in patient GBMs by immunohistochemistry, we demonstrated that the number of Tie2+ vessels increases in recurrent GBM compared with matched untreated tumors. In conclusion, we demonstrate that IR potentiates proangiogenic features of TDEC through the Tie2 signaling pathway, which indicates a new pathway of treatment-induced tumor adaptation. New therapeutic strategies that associate standard treatment and a Tie2 signaling pathway inhibitor should be considered for future trials.

Published
2019

21. RREB1-MKL2 fusion in biphenotypic 'oropharyngeal' sarcoma: New entity or part of the spectrum of biphenotypic sinonasal sarcomas?

Author

Philippe Rochaix, Aurore Siegfried, David Grand, Frédéric Escudié, Claire Romary, Yvan Nicaise, Christine Chevreau, Emmanuelle Uro-Coste, Sophie Le Guellec, Sébastien Vergez, Jean-Michel Coindre, and Béatrice Herbault Barres

Subjects
Male, 0301 basic medicine, Cancer Research, Oncogene Proteins, Fusion, PAX3, Soft Tissue Neoplasms, Biology, medicine.disease_cause, S100 protein, Fusion gene, 03 medical and health sciences, 0302 clinical medicine, Biomarkers, Tumor, Genetics, medicine, Humans, Oncogene Fusion, Gene, Transcription factor, Sarcoma, Middle Aged, medicine.disease, DNA-Binding Proteins, Oropharyngeal Neoplasms, 030104 developmental biology, 030220 oncology & carcinogenesis, Cancer research, Spindle cell sarcoma, Gene Fusion, Carcinogenesis, Paranasal Sinus Neoplasms, Transcription Factors
Abstract

An increasing number of sarcomas displaying a primitive, monomorphic spindle cell phenotype have been shown to harbor recurrent gene fusions, including biphenotypic sinonasal sarcoma (SNS). Occurring in the sinonasal area of middle-aged patients, SNS is a locally aggressive tumor harboring in 90% of cases recurrent gene fusions involving the PAX3 gene, in which the chimeric transcription factor induces an aberrant dual myogenic and neural phenotype. Here, we report an unusual oropharyngeal monomorphic spindle cell sarcoma in a 53-year-old man that revealed a novel RREB1-MKL2 gene fusion by RNA sequencing with the Illumina TruSight RNA Fusion Panel. The gene fusion was validated by RT-PCR. Although the tumor location is unusual (but head and neck seated), most of the other clinical, morphologic, immunophenotypic (focal combined expression of S100 protein, SMA, desmin, and myogenin) and oncogenic data suggest that this biphenotypic "oropharyngeal" sarcoma is closely related to the biphenotypic SNS spectrum. Notably, the RREB1-MKL2 chimeric transcription factor encoded by this fusion gene produced an increase in MKL2 expression, which regulates both neural and myogenic differentiation, mimicking the crucial role of PAX3 reported in SNS oncogenesis. NGS and especially RNA sequencing may be used to identify new candidate fusion oncogenes in soft tissue tumors, which would help in updating the existing classification. In turn, this would lead to better therapeutic management of patients.

Published
2018

22. Ionizing radiation induces endothelial transdifferentiation of glioblastoma stem-like cells through the Tie2 signaling pathway

Author

Florent Arnauduc, Dorian Larrieu, Aurore Siegfried, Marie Tosolini, Yvan Nicaise, Solène M. Evrard, Elizabeth Cohen-Jonathan Moyal, Christine Toulas, Anthony Lemarié, Monique Courtade-Saïdi, Laure Malric, and Pauline Deshors

Subjects
biology, Chemistry, Kinase, Transdifferentiation, Angiopoietin receptor, In vitro, Transcriptome, Neurosphere, embryonic structures, cardiovascular system, biology.protein, Cancer research, Immunohistochemistry, Anatomy, Signal transduction
Abstract

Glioblastomas (GBM) are brain tumors with a poor prognosis despite treatment that combines surgical resection and radio-chemotherapy. These tumors are characterized by abundant vascularization and significant cellular heterogeneity including GBM stem-like cells (GSC) which contribute to tumor aggressiveness, resistance, and recurrence. Recent data has demonstrated that GSC are directly involved in the formation of new vessels via their transdifferentiation into Tumor Derived Endothelial Cells (TDEC). We postulate that cellular stress such as ionizing radiation (IR) could enhance the transdifferentiation of GSC into TDEC. GSC neurospheres isolated from 3 different patients were irradiated or not and were then transdifferentiated into TDEC. In fact, TDEC obtained from irradiated GSC (TDEC IR + ) migrate more towards VEGF, form more pseudotubes in MatrigelTM in vitro and develop more functional blood vessels in MatrigelTM plugs implanted in Nude mice than TDEC obtained from non-irradiated GSC. Transcriptomic analysis allows us to highlight an overexpression of Tie2 in TDEC IR+. All IR-induced effects on TDEC were abolished by using a Tie2 kinase inhibitor, which confirms the role of the Tie2 signaling pathway in this process. Finally, by analyzing Tie2 expression in patient GBMs by immunohistochemistry, we demonstrated that the number of Tie2+ vessels increases in recurrent GBM compared with matched untreated tumors. In conclusion, we demonstrate that IR potentiates proangiogenic features of TDEC through the Tie2 signaling pathway, which indicates a new pathway of treatment-induced tumor adaptation. New therapeutic strategies that associate standard treatment and a Tie2 signaling pathway inhibitor should be considered for future trials.

Published
2021

23. EWSR1-PATZ1 gene fusion may define a new glioneuronal tumor entity

Author

Anne-Isabelle Bertozzi, Emmanuelle Uro-Coste, Claude-Alain Maurage, Sarah Péricart, Sergio Boetto, Yvan Nicaise, Sophie Le Guellec, Camille Franchet, Alix Delrieu, Matthieu Vinchon, David Grand, Frédéric Escudié, David T.W. Jones, Valérie Rigau, Anne Gomez-Brouchet, Aurore Siegfried, Jean-Christophe Sol, Audrey Rousseau, Franck-Emmanuel Roux, Dominique Figarella-Branger, Département de Pathologie [CHU Toulouse], CHU Toulouse [Toulouse], Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Design and Application of Innovative Local Treatments in Glioblastoma (CRCINA-ÉQUIPE 17), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Département de Pathologie [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Département de Pathologie [CHRU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut Claudius-Regaud [IUCT, Toulouse], Institut Universitaire du Cancer Toulouse - Oncopôle (IUCT), Département de Neurochirurgie [CHU Toulouse], Département de Neurochirurgie[Lille], Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Toulouse Neuro Imaging Center (ToNIC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Département de Pathologie [Centre Médical Universitaire Montpellier], Centre Médical Universitaire Montpellier - CMUM, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'Oncopédiatrie [CHU Toulouse], Hopp Children's Cancer Center Heidelberg [Heidelber, Germany] (KITZ), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ)-Heidelberg University Hospital [Heidelberg], Division of Pediatric Neurooncology [Heidelberg, Germany], German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ)-German Cancer Consortium [Heidelberg] (DKTK), Département de Pathologie [CHU Marseille], CHU Marseille, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), D. Jones is supported by funding for the Everest Centre for Paediatric Low- Grade Brain Tumour Research through the Brain Tumour Charity (UK). We are grateful to Karen Silva for her help in handling tumor samples from the different pathological departments. Samples from Marseille were retrieved from the AP-HM tumor bank AC 2017:1786. Samples from Toulouse were retrieved from the CHU de Toulouse tumor bank BB-0033-00014., Service Anatomie et cytologie pathologiques [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Neurochirurgie [CHU Toulouse], Pôle Neurosciences [CHU Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Sercice Hématologie, immunologie et oncologie pédiatrique [CHU Toulouse], Pôle Enfants [CHU Toulouse], Bernardo, Elizabeth, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Design and Application of Innovative Local Treatments in Glioblastoma (CRCINA - Département NOHMAD - Equipe 17), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers (CRCINA), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre de recherche Jean-Pierre Aubert-Neurosciences et Cancer, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Institut pour la Recherche sur le Cancer de Lille (U837 INSERM - IRCL), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche Jean-Pierre AUBERT - Neurosciences et Cancer -JPArc [Lille], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hopp Children's Cancer Center at the NCT Heidelberg - KiTZ [Heidelber, Germany]g, Centre de Recherche en Cancérologie de Toulouse ( CRCT ), Université Paul Sabatier - Toulouse 3 ( UPS ) -CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Design and Application of Innovative Local Treatments in Glioblastoma ( CRCINA - Département NOHMAD - Equipe 17 ), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers ( CRCINA ), Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Centre hospitalier universitaire d'Angers ( CHU Angers ), Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé, Institut pour la Recherche sur le Cancer de Lille ( U837 INSERM - IRCL ), Institut pour la recherche sur le cancer de Lille [Lille] ( IRCL ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre de Recherche Jean-Pierre AUBERT - Neurosciences et Cancer -JPArc [Lille], Institut de pharmacologie et de biologie structurale ( IPBS ), Université Paul Sabatier - Toulouse 3 ( UPS ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Universitaire du Cancer Toulouse - Oncopôle ( IUCT ), Centre Hospitalier Universitaire de Toulouse - CHU Toulouse (FRANCE), Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Toulouse Neuro Imaging Center ( ToNIC ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Purpan - Centre Hospitalier Universitaire (CHU) de Toulouse-Université Toulouse III - Paul Sabatier, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs ( INM ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), German Cancer Research Center ( DKFZ ) -German Cancer Consortium - DKTK [Heidelberg, Germany], Institut de neurophysiopathologie ( INP ), and Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS )

Subjects
0301 basic medicine, Adult, Male, DNA Copy Number Variations, Kruppel-Like Transcription Factors, Locus (genetics), [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Pathology and Forensic Medicine, Ganglioglioma, Fusion gene, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Glioma, medicine, Biomarkers, Tumor, Humans, Copy-number variation, Child, In Situ Hybridization, Fluorescence, Research Articles, Sanger sequencing, Brain Neoplasms, General Neuroscience, Methylation, DNA Methylation, medicine.disease, Neoplasms, Neuroepithelial, 3. Good health, Repressor Proteins, 030104 developmental biology, Fusion transcript, Cancer research, symbols, Female, Neurology (clinical), Gene Fusion, RNA-Binding Protein EWS, 030217 neurology & neurosurgery
Abstract

International audience; We investigated the challenging diagnostic case of a ventricular cystic glioneuronal tumor with papillary features, by RNA sequencing using the Illumina TruSight RNA Fusion panel. We did not retrieve the SLC44A1-PRKCA fusion gene specific for papillary glioneuronal tumor, but an EWSR1-PATZ1 fusion transcript. RT-PCR followed by Sanger sequencing confirmed the EWSR1-PATZ1 fusion. It matched with canonic EWSR1 fusion oncogene, juxtaposing the entire N terminal transcriptional activation domain of EWSR1 gene and the C terminal DNA binding domain of a transcription factor gene, PATZ1. PATZ1 protein belongs to the BTB-ZF (broad-complex, tramtrack and bric-à-brac -zinc finger) family. It directly regulates Pou5f1 and Nanog and is essential to maintaining stemness by inhibiting neural differentiation. EWSR1-PATZ1 fusion is a rare event in tumors: it was only reported in six round cell sarcomas and in three gliomas of three exclusively molecular studies. The first reported glioma was a BRAF[V600E] negative ganglioglioma, the second a BRAF[V600E] negative glioneuronal tumor, not otherwise specified, and the third, very recently reported, a high grade glioma, not otherwise specified. In our study, forty BRAF[V600E] negative gangliogliomas were screened by FISH using EWSR1 break-apart probes. We performed methylation profiling for the index case and for seven out of the ten FISH positive cases. The index case clustered apart from other pediatric low grade glioneuronal entities, and specifically from the well-defined ganglioglioma methylation group. An additional pediatric intraventricular ganglioglioma clustered slightly more closely with ganglioglioma, but showed differences from the main ganglioglioma group and similarities with the index case. Both cases harbored copy number variations at the PATZ1 locus. EWSR1-PATZ1 gene fusion might define a new type of glioneuronal tumors, distinct from gangliogliomas.

Published
2019

24. Cardioprotective Angiotensin-(1-7) Peptide Acts as a Natural-Biased Ligand at the Angiotensin II Type 1 Receptor

Author

Jean-Michel Senard, Marie-Hélène Seguelas, Du N’Guyen, Caroline Dubroca, Jean-Louis Banères, Céline M'Kadmi, Yvan Nicaise, Céline Galés, Atul Pathak, Cédric Boularan, Colette Denis, Claire Pilette, Ségolène Galandrin, and Jacky Marie

Subjects
0301 basic medicine, Biased ligand, medicine.medical_specialty, Cardiotonic Agents, Peptide, Receptor, Angiotensin, Type 2, Sensitivity and Specificity, Renin-Angiotensin System, 03 medical and health sciences, Phenylephrine, Internal medicine, Renin–angiotensin system, Internal Medicine, medicine, Functional selectivity, Animals, Humans, Aorta, Abdominal, Receptor, Cells, Cultured, beta-Arrestins, G protein-coupled receptor, chemistry.chemical_classification, Angiotensin 1, Angiotensin II, Muscles, Peptide Fragments, 030104 developmental biology, Endocrinology, HEK293 Cells, chemistry, Vasoconstriction, cardiovascular system, Angiotensin I, hormones, hormone substitutes, and hormone antagonists, Signal Transduction
Abstract

Hyperactivity of the renin–angiotensin–aldosterone system through the angiotensin II (Ang II)/Ang II type 1 receptor (AT1-R) axis constitutes a hallmark of hypertension. Recent findings indicate that only a subset of AT1-R signaling pathways is cardiodeleterious, and their selective inhibition by biased ligands promotes therapeutic benefit. To date, only synthetic biased ligands have been described, and whether natural renin–angiotensin–aldosterone system peptides exhibit functional selectivity at AT1-R remains unknown. In this study, we systematically determined efficacy and potency of Ang II, Ang III, Ang IV, and Ang-(1–7) in AT1-R–expressing HEK293T cells on the activation of cardiodeleterious G-proteins and cardioprotective β-arrestin2. Ang III and Ang IV fully activate similar G-proteins than Ang II, the prototypical AT1-R agonist, despite weaker potency of Ang IV. Interestingly, Ang-(1–7) that binds AT1-R fails to promote G-protein activation but behaves as a competitive antagonist for Ang II/Gi and Ang II/Gq pathways. Conversely, all renin–angiotensin–aldosterone system peptides act as agonists on the AT1-R/β-arrestin2 axis but display biased activities relative to Ang II as indicated by their differences in potency and AT1-R/β-arrestin2 intracellular routing. Importantly, we reveal Ang-(1–7) a known Mas receptor-specific ligand, as an AT1-R–biased agonist, selectively promoting β-arrestin activation while blocking the detrimental Ang II/AT1-R/Gq axis. This original pharmacological profile of Ang-(1–7) at AT1-R, similar to that of synthetic AT1-R–biased agonists, could, in part, contribute to its cardiovascular benefits. Accordingly, in vivo, Ang-(1–7) counteracts the phenylephrine-induced aorta contraction, which was blunted in AT1-R knockout mice. Collectively, these data suggest that Ang-(1–7) natural-biased agonism at AT1-R could fine-tune the physiology of the renin–angiotensin–aldosterone system.

Published
2016

25. MB-77MOLECULAR SUBGROUPING OF MEDULLOBLASTOMA WITH NANOSTRING TECHNOLOGY: A FEASIBILITY STUDY FOR ROUTINE REAL-TIME PROCEDURES

Author

David Gentien, Debbie Hicks, Gaëlle Pierron, Steve Clifford, Julien Masliah-Planchon, Dominique Figarella-Branger, Marie-Bernadette Delisle, Benoit Albaud, Christelle Dufour, Teva Riou, François Doz, Yvan Nicaise, Franck Bourdeaut, and Olivier Delattre

Subjects
Medulloblastoma, Cancer Research, medicine.medical_specialty, Abstracts, Text mining, Oncology, Computer science, business.industry, medicine, Medical physics, Neurology (clinical), business, medicine.disease
Published
2016

26. Characteristics of lung cancer in women: Importance of hormonal and growth factors

Author

Camille Allera, Julie Milia, Isabelle Rouquette, Yvan Nicaise, Gilles Favre, Julie Laurent, Laurent Brouchet, Marie-Bernadette Delisle, Julien Mazieres, Alain Didier, and Valérie Lauwers-Cances

Subjects
Adult, Male, Pulmonary and Respiratory Medicine, Oncology, Cancer Research, medicine.medical_specialty, Lung Neoplasms, Receptor, ErbB-2, Estrogen receptor, medicine.disease_cause, Sex Factors, Internal medicine, medicine, Humans, Hormone metabolism, Receptor, Lung cancer, Aged, Neoplasm Staging, Lung, business.industry, Middle Aged, Prognosis, medicine.disease, Hormones, ErbB Receptors, Endocrinology, medicine.anatomical_structure, Receptors, Estrogen, Mutation, Intercellular Signaling Peptides and Proteins, Biomarker (medicine), Female, business, Carcinogenesis, Hormone
Abstract

Based on epidemiological, clinical, and preclinical data, lung carcinogenesis can be distinctive in women, suggesting that women should be treated differently depending on the expression of various specific biomarkers. We aimed to describe the hormonal and genetic profile of lung cancer in both men and women to identify gender specificities. Primary lung-tumor tissues from surgically treated patients, (50 men, 50 women) were analyzed and compared for expression of estrogen receptors (ER) α and β, progesterone receptors (PR), epidermal growth-factor receptor (EGFR), and HER2 (for EGFR and K-Ras mutations). These data were combined with clinical and outcome data. Fewer women with lung cancer were smokers (p=0.001) and they smoked fewer cigarettes (p=0.001). We observed a higher rate of EGFR mutations (p=0.02) and ERα expression (p=0.006) in women. ERβ and EGFR were also expressed more frequently in women (p=0.29 and p=0.16). HER2 was overexpressed regardless of gender in three men and two women. K-Ras was mutated in 16% of both men and women. Interestingly, there was a positive link between EGFR expression and expression of ERα (p=0.028) and ERβ (p=0.047) in both men and women. Expression of ERα was associated with improved disease-free survival (p=0.007). Our findings provide further evidence on the specificities of lung cancer in women. The differential expression of specific biomarkers, which could be targeted by therapy, favors the development of gender-based treatment guided by biomarker expression.

Published
2012

27. Colony induction and growth inhibition in Desmodesmus quadrispina (Chlorococcales) by allelochemicals released from the filamentous alga Uronema confervicolum (Ulotrichales)

Author

Joséphine Leflaive, Yvan Nicaise, Loïc Ten-Hage, and Gérard Lacroix

Subjects
0106 biological sciences, 0303 health sciences, biology, 010604 marine biology & hydrobiology, fungi, Ulotrichales, Biofilm, Context (language use), Desmodesmus, Chlorococcales, biology.organism_classification, 01 natural sciences, Microbiology, Monoraphidium, 03 medical and health sciences, Algae, Botany, 14. Life underwater, Ecology, Evolution, Behavior and Systematics, Allelopathy, 030304 developmental biology
Abstract

In biofilms, the competition between microorganisms for light, nutrients and space is extreme. Moreover, planktonic algae can be considered as competitors insofar as they decrease the available light for the benthic algae. One of the strategies employed by microorganisms to eliminate competitors is the release of inhibiting compounds, a process known as allelopathy. Here we demonstrate that a benthic/epiphytic alga, Uronema confervicolum, produces allelopathic compounds that induce oxidative stress and growth inhibition in the planktonic Desmodesmus quadrispina. Some of these compounds can also trigger the formation of colony in D. quadrispina. As colonies have higher sedimentation rates than unicells, their induction by U. confervicolum might decrease shading. This study is the first report of colony induction in the context of alga-alga interaction. Our results also suggest the implication of mitogen-activated protein (MAP) kinases in the transduction of the signal leading to the formation of reactive oxygen species in the cells. A comparison with allelochemicals from another planktonic green alga, Monoraphidium aff. dybowski, emphasizes the specificity of colony induction by U. confervicolum, in contrast with oxidative stress which is induced by several compounds. The reciprocal production of inhibiting compounds by D. quadrispina makes this interaction an interesting example of co-evolution between two microorganisms belonging to different compartments of the ecosystem.

Published
2008

28. Reduced sphingosine kinase-1 and enhanced sphingosine 1-phosphate lyase expression demonstrate deregulated sphingosine 1-phosphate signaling in Alzheimer's disease

Author

Johnatan Ceccom, Claude Alain Maurage, Yvan Nicaise, Olivier Cuvillier, Stuart M. Pitson, Charles Duyckaerts, Valérie Lauwers-Cances, Marie-Bernadette Delisle, Catherine Gentil, Najat Loukh, Christian Touriol, Emmanuelle Uro-Coste, Service d'Anatomie Pathologique, CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Service d'Epidémiologie, CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre for Cancer Biology, SA Pathology, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U837 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, Service de Pathologie, Université Lille Nord (France)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], Institut de pharmacologie et de biologie structurale (IPBS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), This work was supported by a grant from the Clinical Research Hospital Program from the French Ministry of Health (PHRC 2010, n° 18_02) and the Fondation Plan Alzheimer., Service Anatomie et cytologie pathologiques [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service Epidémiologie clinique et santé publique [CHU Toulouse], Pôle Santé publique et médecine publique [CHU Toulouse], Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Ceccom, Johnatan, Loukh, Najat, Lauwers-, Cances Valerie, Touriol, Christian, Nicaise, Yvan, Gentil, Catherine, Uro-Coste, Emmanuelle, Pitson, Stuart, Maurage, Claude Alain, Duyckaerts, Charles, Cuvillier, Olivier, Delisle, Marie-Bernadette, and BMC, Ed.

Subjects
Male, Statistics as Topic, chemistry.chemical_compound, 0302 clinical medicine, Receptor, Neuropathology, Aged, 80 and over, Neurons, 0303 health sciences, sphingoising1-phosphate lyase-neuropatholgy, Neurodegeneration, Brain, Sphingosine kinase-1, Middle Aged, Alzheimer's disease, Cell biology, Sphingosine 1-phosphate lyase, Phosphotransferases (Alcohol Group Acceptor), Biochemistry, Sphingosine kinase 1, sphingosine kinase-1, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Alzheimer’s disease, Alzheimer ' s disease, Signal Transduction, beta amyloid, Biology, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, Alzheimer Disease, medicine, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Sphingosine-1-phosphate, Aged, Aldehyde-Lyases, 030304 developmental biology, Sphingolipids, Amyloid beta-Peptides, sphingolipids, Sphingosine, Cell growth, Research, Beta amyloid, Lipid signaling, medicine.disease, Sphingolipid, Gene Expression Regulation, chemistry, biology.protein, Neurology (clinical), 030217 neurology & neurosurgery
Abstract

International audience; BACKGROUND: The accumulation of beta amyloid (Aβ) peptides, a hallmark of Alzheimer's disease (AD) is related to mechanisms leading to neurodegeneration. Among its pleiotropic cellular effects, Aβ accumulation has been associated with a deregulation of sphingolipid metabolism. Sphingosine 1-phosphate (S1P) derived from sphingosine is emerging as a critical lipid mediator regulating various biological activities including cell proliferation, survival, migration, inflammation, or angiogenesis. S1P tissue level is low and kept under control through equilibrium between its synthesis mostly governed by sphingosine kinase-1 (SphK1) and its degradation by sphingosine 1-phosphate lyase (SPL). We have previously reported that Aβ peptides were able to decrease the activity of SphK1 in cell culture models, an effect that could be blocked by the prosurvival IGF-1/IGF-1R signaling. RESULTS: Herein, we report for the first time the expression of both SphK1 and SPL by immunohistochemistry in frontal and entorhinal cortices from 56 human AD brains. Immunohistochemical analysis revealed a decreased expression of SphK1 and an increased expression of SPL both correlated to amyloid deposits in the entorhinal cortex. Otherwise, analysis of brain tissue extracts showed a decrease of SphK1 expression in AD brains whereas SPL expression was increased. The content of IGF-1R, an activator of SphK1, was found decreased in AD brains as well as S1P1, the major receptor for S1P. CONCLUSIONS: Collectively, these results highlight the importance of S1P in AD suggesting the existence of a global deregulation of S1P signaling in this disease from its synthesis by SphK1 and degradation by SPL to its signaling by the S1P1 receptor.

Published
2014

29. Temporal Dynamics of River Biofilm in Constant Flows: A Case Study in a Riverside Laboratory Flume

Author

Frédéric Garabetian, Yvan Bercovitz, Stéphanie Boulêtreau, Mehdi Sellali, Frédéric Moulin, Olivier Eiff, Sabine Sauvage, José-Miguel Sánchez-Pérez, Yvan Nicaise, Arturo Elosegi, Centre National de la Recherche Scientifique - CNRS (FRANCE), Institut National Polytechnique de Toulouse - INPT (FRANCE), Université de Bordeaux 1 (FRANCE), Université Toulouse III - Paul Sabatier - UT3 (FRANCE), Universidad del País Vasco - Euskal Herriko Unibertsitatea - EHU (SPAIN), Ecole Pratique des Hautes Etudes - EPHE (FRANCE), Université Montesquieu - Bordeaux 4 (FRANCE), and Institut National Polytechnique de Toulouse - Toulouse INP (FRANCE)

Subjects
Hydrology, Epilithon, Experimental flume, Primary production, Biofilm matrix, Aquatic Science, Silt, Flume, Océan, Atmosphère, Periphyton, Aquatic plant, Botany, Bacterial community fingerprinting, Environmental science, Dominance (ecology), Water quality, Community metabolism, Ecology, Evolution, Behavior and Systematics
Abstract

A 15-week experiment was performed in a riverside laboratory flume (with diverted river water) to check variations of river biofilm structure (biomass, algal and bacterial compositions) and function (community gross primary production GPP and respiration) under constant flow while water quality went through natural temporal variations. One major suspended matter pulse coinciding with one river flood was recorded after 10 weeks of experiment. Epilithic biofilm first exhibited a 10-week typical pattern of biomass accrual reaching 33 g ash-free dry matter (AFDM) m–2 and 487 mg chlorophyll-a m–2 and then, experienced a shift to dominance of loss processes (loss of 60% AFDM and 80% chlorophyll-a) coinciding with the main suspended matter pulse. Algal diversity remained low and constant during the experiment: Fragilaria capucina and Encyonema minutum always contribute over 80% of cell counts. DGGE banding patterns discriminated between two groups that corresponded to samples before and after biomass loss, indicating major changes in the bacterial community composition. GPP/R remained high during the experiment, suggesting that photoautotrophic metabolism prevailed and detachment was not autogenic (i.e., due to algal senescence or driven by heterotrophic processes within the biofilm). Observational results suggested that silt deposition into the biofilm matrix could have triggered biomass loss.

Published
2010

30. Characterization of humoral and cellular immune responses in mice induced by immunization with HIV-1 Nef regulatory protein encapsulated in poly(DL-lactide-co-glycolide) microparticles

Author

Elmostafa Bahraoui, Marinette Moynier, Sophie Barthelemy, Yvan Nicaise, Muriel Aussillous, Yamina Bennasser, Luc Montagnier, Pierre-Louis Vidal, and Corinne Moureau

Subjects
HIV Antigens, Polymers, viruses, medicine.medical_treatment, T-Lymphocytes, Immunology, Freund's Adjuvant, Spleen, HIV Antibodies, Lymphocyte Activation, Epitope, Immunoglobulin G, Gene Products, nef, Mice, Immune system, Polylactic Acid-Polyglycolic Acid Copolymer, medicine, Animals, Lactic Acid, nef Gene Products, Human Immunodeficiency Virus, Molecular Biology, Cells, Cultured, Mice, Inbred BALB C, biology, virus diseases, Virology, Molecular biology, In vitro, Microspheres, medicine.anatomical_structure, Freund's adjuvant, biology.protein, HIV-1, Cytokines, Epitopes, B-Lymphocyte, Female, Immunization, Antibody, Adjuvant, Polyglycolic Acid
Abstract

We have characterized the humoral and cellular immune responses of BALB/c mice immunized with HIV-1 Nef regulatory protein encapsulated in poly(DL-lactide-co-glycolide) PLG particles. Three groups of mice were immunized with Nef PLG, Nef in the presence of complete Freund's adjuvant (CFA) or Nef alone in PBS. When titers were compared 7 months after the last injection, anti-Nef titers in mice immunized with Nef PLG were still close to the maximum, whereas a significant decrease was observed in mice immunized with Nef alone (five times lower) or with Nef in CFA (three times lower). These results indicate that Nef PLG is at least a similar or better vector/adjuvant than Nef in CFA concerning the duration of the humoral immune response. The analysis of cytokine profiles (IL-5 and IL-10) and the isotypic patterns of anti-Nef antibodies (predominantly IgG1), in the three groups of mice, indicated a predominant Th2 immune response. Using synthetic peptides covering the entire sequence of Nef, we identified at least three linear epitopes within sequences 32-64, 118-167 and 185-205 in the sera of mice immunized with Nef PLG or Nef CFA. In contrast, anti-Nef antibodies against Nef alone failed to recognize synthetic peptides, indicating that the majority of anti-Nef antibodies were primarily directed against conformational epitopes. We then examined the ability of Nef PLG to prime for the antigen-specific proliferative responses in vitro. The data obtained indicate the presence of both B-cell and T-cell epitopes in the C-terminal fragment of the protein after immunization of mice with Nef encapsulated in PLG particles.

Published
2002

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