Systemic AA amyloidosis caused by inflammatory hepatocellular adenoma

To the Editor: Amyloid A (AA) systemic amyloidosis is a complication of chronic inflammatory diseases that is caused by the deposition of insoluble aggregates of cleaved N-terminal fragments of serum amyloid A (SAA) protein in tissues and organs throughout the body. Under physiologic conditions, SAA protein is produced by hepatocytes during the acute inflammatory phase in response to various cytokines such as interleukin-6. SAA is also overexpressed by neoplastic hepatocytes in inflammatory hepatocellular adenomas, a specific molecular subtype of benign liver tumors

BecA-ILRI Hub capacity building program: Empowering African scientists and institutions to solve Africa’s agricultural challenges

<p>Bars show medians, *p<0.05, **p<0.01 Dunn's tests vs. controls. # p<0.05 two-tails, Mann-Whitney -test vs. controls.</p

Increased Immune Complexes of Hypocretin Autoantibodies in Narcolepsy

International audienceBACKGROUND: Hypocretin peptides participate in the regulation of sleep-wake cycle while deficiency in hypocretin signaling and loss of hypocretin neurons are causative for narcolepsy-cataplexy. However, the mechanism responsible for alteration of the hypocretin system in narcolepsy-cataplexy and its relevance to other central hypersomnias remain unknown. Here we studied whether central hypersomnias can be associated with autoantibodies reacting with hypocretin-1 peptide present as immune complexes. METHODOLOGY: Serum levels of free and dissociated (total) autoantibodies reacting with hypocretin-1 peptide were measured by enzyme-linked immunosorbent assay and analyzed with regard to clinical parameters in 82 subjects with narcolepsy-cataplexy, narcolepsy without cataplexy or idiopathic hypersomnia and were compared to 25 healthy controls. PRINCIPAL FINDINGS: Serum levels of total but not free IgG autoantibodies against hypocretin-1 were increased in narcolepsy-cataplexy. Increased levels of complexed IgG autoantibodies against hypocretin-1 were found in all patients groups with a further increase in narcolepsy-cataplexy. Levels of total IgM hypocretin-1 autoantibodies were also elevated in all groups of patients. Increased levels of anti-idiotypic IgM autoantibodies reacting with hypocretin-1 IgG autoantibodies affinity purified from sera of subjects with narcolepsy-cataplexy were found in all three groups of patients. Disease duration correlated negatively with serum levels of hypocretin-1 IgG and IgM autoantibodies and with anti-idiotypic IgM autoantibodies. CONCLUSION: Central hypersomnias and particularly narcolepsy-cataplexy are characterized by higher serum levels of autoantibodies directed against hypocretin-1 which are present as immune complexes most likely with anti-idiotypic autoantibodies suggesting their relevance to the mechanism of sleep-wake cycle regulation

Origin and functional consequences of structural variations in liver tumorigenesis

Liver cancers are extremely heterogeneous, with a wide spectrum of etiologies, histological characteristics and deregulated biological pathways. Large-scale sequencing projects in the last decade revealed numerous driver mutations and copy-number changes. However, the role of structural variations (SVs) in liver tumorigenesis is still poorly understood. During my PhD project, I developed innovative computational approaches integrating whole genome and RNA sequencing data to identify new driver SVs in liver cancers. I unraveled recurrent fusions involving ROS1 and FRK oncogenes, leading to a constitutive activation of the JAK/STAT pathway and to the development of inflammatory hepatocellular adenomas (HCA). I also described an original oncogenic mechanism involving the loss of post-transcriptional regulatory elements leading to a massive overexpression of IL6 in a clinical case of inflammatory HCA associated with amyloidosis. Finally, I identified driver SVs affecting regulatory elements in hepatocellular carcinomas (HCC), including enhancer hijacking events activating CCNE1 or TERT oncogenes.To better understand the origin of SVs, I implemented a signature analysis framework considering the nature and size of SVs identified in each tumor. This approach allowed me to highlight HCC subgroups with particular SV signatures. In particular, I discovered a new clinico-molecular HCC subgroup driven by the activation of CCNA2 or CCNE1 by various mechanisms. These tumors (CCN-HCC) represent 7% of HCC and display a specific pattern of rearrangements (signature RS1) related to replication stress, with hundreds of focal duplications and templated insertion cycles. CCN-HCC are aggressive tumors but may be targetable by inhibitors of ATR response to replication stress. Altogether, this work helps to refine the molecular characterization of both benign and malignant liver tumor by revealing new driver genes and molecular mechanisms. Those findings have clinical implications, as the definition of homogeneous cancer subgroups is essential to develop efficient tailored therapiesLe cancer du foie est très hétérogène, avec un large spectre d'étiologies, de caractéristiques histologiques et de voies biologiques dérégulées. Les projets de séquençage à grande échelle réalisés durant la dernière décennie ont révélé de nombreuses mutations driver et des changements du nombre de copies. Cependant, le rôle des variant structuraux (VS) dans la tumorigénèse du foie est encore mal compris. Au cours de mon projet de doctorat, j'ai développé des approches informatiques innovantes intégrant des données de séquençage du génome entier et de l'ARN pour identifier de nouveaux variant structuraux dans les cancers du foie. J'ai mis au jour des fusions récurrentes impliquant des oncogènes ROS1 et FRK, conduisant à une activation constitutive de la voie JAK/STAT et au développement d'adénomes hépatocellulaires inflammatoires (AHC). J'ai également décrit un mécanisme oncogène original impliquant la perte d'éléments régulateurs post-transcriptionnels, conduisant à une surexpression massive d’IL6 dans un cas clinique d'AHC inflammatoire associé à l'amylose. Enfin, j'ai identifié les VS driver affectant les éléments régulateurs dans les carcinomes hépatocellulaires (CHC), y compris les événements d’enhancer hijacking activant les oncogènes CCNE1 ou TERT.Afin de mieux comprendre l'origine des VS, j'ai mis en place un cadre d'analyse de signature prenant en compte la nature et la taille des variation structuraux identifiées dans chaque tumeur. Cette approche m'a permis de mettre en évidence les sous-groupes de HCC présentant des signatures de VS particulières. En particulier, j'ai découvert un nouveau sous-groupe de CHC clinique-moléculaire qui est caractérisé par l'activation de CCNA2 ou CCNE1 par des mécanismes drivers. Ces tumeurs (CCN-HCC) représentent 7% des carcinomes hépatocellulaire et présentent une signature spécifique de réarrangements (signature RS1) liés au stress réplicatif, avec des centaines de duplications focales et des « Template Insertion Cycles ». Les CCN-HCC sont des tumeurs agressives mais peuvent être ciblées par des inhibiteurs de la réponse ATR au stress réplicatif. Dans l'ensemble, ces travaux contribuent à affiner la caractérisation moléculaire des tumeurs hépatiques bénignes et malignes en révélant de nouveaux gènes drivers et mécanismes moléculaires. Ces résultats ont des implications cliniques, car la définition de sous-groupes homogènes de cancers est essentielle pour développer des thérapies efficaces et adaptée

Origine et conséquences fonctionnelles des variant structuraux dans la tumorigénèse hépatique

Le cancer du foie est très hétérogène, avec un large spectre d'étiologies, de caractéristiques histologiques et de voies biologiques dérégulées. Les projets de séquençage à grande échelle réalisés durant la dernière décennie ont révélé de nombreuses mutations driver et des changements du nombre de copies. Cependant, le rôle des variant structuraux (VS) dans la tumorigénèse du foie est encore mal compris. Au cours de mon projet de doctorat, j'ai développé des approches informatiques innovantes intégrant des données de séquençage du génome entier et de l'ARN pour identifier de nouveaux variant structuraux dans les cancers du foie. J'ai mis au jour des fusions récurrentes impliquant des oncogènes ROS1 et FRK, conduisant à une activation constitutive de la voie JAK/STAT et au développement d'adénomes hépatocellulaires inflammatoires (AHC). J'ai également décrit un mécanisme oncogène original impliquant la perte d'éléments régulateurs post-transcriptionnels, conduisant à une surexpression massive d’IL6 dans un cas clinique d'AHC inflammatoire associé à l'amylose. Enfin, j'ai identifié les VS driver affectant les éléments régulateurs dans les carcinomes hépatocellulaires (CHC), y compris les événements d’enhancer hijacking activant les oncogènes CCNE1 ou TERT.Afin de mieux comprendre l'origine des VS, j'ai mis en place un cadre d'analyse de signature prenant en compte la nature et la taille des variation structuraux identifiées dans chaque tumeur. Cette approche m'a permis de mettre en évidence les sous-groupes de HCC présentant des signatures de VS particulières. En particulier, j'ai découvert un nouveau sous-groupe de CHC clinique-moléculaire qui est caractérisé par l'activation de CCNA2 ou CCNE1 par des mécanismes drivers. Ces tumeurs (CCN-HCC) représentent 7% des carcinomes hépatocellulaire et présentent une signature spécifique de réarrangements (signature RS1) liés au stress réplicatif, avec des centaines de duplications focales et des « Template Insertion Cycles ». Les CCN-HCC sont des tumeurs agressives mais peuvent être ciblées par des inhibiteurs de la réponse ATR au stress réplicatif. Dans l'ensemble, ces travaux contribuent à affiner la caractérisation moléculaire des tumeurs hépatiques bénignes et malignes en révélant de nouveaux gènes drivers et mécanismes moléculaires. Ces résultats ont des implications cliniques, car la définition de sous-groupes homogènes de cancers est essentielle pour développer des thérapies efficaces et adaptéesLiver cancers are extremely heterogeneous, with a wide spectrum of etiologies, histological characteristics and deregulated biological pathways. Large-scale sequencing projects in the last decade revealed numerous driver mutations and copy-number changes. However, the role of structural variations (SVs) in liver tumorigenesis is still poorly understood. During my PhD project, I developed innovative computational approaches integrating whole genome and RNA sequencing data to identify new driver SVs in liver cancers. I unraveled recurrent fusions involving ROS1 and FRK oncogenes, leading to a constitutive activation of the JAK/STAT pathway and to the development of inflammatory hepatocellular adenomas (HCA). I also described an original oncogenic mechanism involving the loss of post-transcriptional regulatory elements leading to a massive overexpression of IL6 in a clinical case of inflammatory HCA associated with amyloidosis. Finally, I identified driver SVs affecting regulatory elements in hepatocellular carcinomas (HCC), including enhancer hijacking events activating CCNE1 or TERT oncogenes.To better understand the origin of SVs, I implemented a signature analysis framework considering the nature and size of SVs identified in each tumor. This approach allowed me to highlight HCC subgroups with particular SV signatures. In particular, I discovered a new clinico-molecular HCC subgroup driven by the activation of CCNA2 or CCNE1 by various mechanisms. These tumors (CCN-HCC) represent 7% of HCC and display a specific pattern of rearrangements (signature RS1) related to replication stress, with hundreds of focal duplications and templated insertion cycles. CCN-HCC are aggressive tumors but may be targetable by inhibitors of ATR response to replication stress. Altogether, this work helps to refine the molecular characterization of both benign and malignant liver tumor by revealing new driver genes and molecular mechanisms. Those findings have clinical implications, as the definition of homogeneous cancer subgroups is essential to develop efficient tailored therapie

RSPO2 abnormal transcripts result from read-through in liver tumours with high ß-catenin activation and CTNNB1 mutations

International audienceThomas Longerich and collaborators1 recently published an intriguing observation in hepatocellular adenoma (HCA) showing an activation of the Wnt/ß-catenin signalling pathway without CTNNB1 or APC mutations. The authors identified a recurrent deletion leading to a fusion between a short interspersed nuclear element (SINE) sequence and RSPO2 gene in three HCAs and three hepatocellular carcinomas (HCCs) all activated for ß-catenin, including one tumour with CTNNB1 mutations and five tumours without APC or CTNNB1 mutations. The authors proposed RSPO2fusion as a recurrent mechanism of ß-catenin activation in liver tumourigenesis.Following this original observation, we analysed the expression and rearrangement of RSPO2 in a series of 10 HCAs and 163 HCCs analysed with RNAseq. We identified a correlation of RSPO2 mRNA expression with several genes known to be positively

High Impact: The Role of Promiscuous Binding Sites in Polypharmacology

International audienceThe literature focuses on drug promiscuity, which is a drug's ability to bind to several targets, because it plays an essential role in polypharmacology. However, little work has been completed regarding binding site promiscuity, even though its properties are now recognized among the key factors that impact drug promiscuity. Here, we quantified and characterized the promiscuity of druggable binding sites from protein-ligand complexes in the high quality Mother Of All Databases while using statistical methods. Most of the sites (80%) exhibited promiscuity, irrespective of the protein class. Nearly half were highly promiscuous and able to interact with various types of ligands. The corresponding pockets were rather large and hydrophobic, with high sulfur atom and aliphatic residue frequencies, but few side chain atoms. Consequently, their interacting ligands can be large, rigid, and weakly hydrophilic. The selective sites that interacted with one ligand type presented less favorable pocket properties for establishing ligand contacts. Thus, their ligands were highly adaptable, small, and hydrophilic. In the dataset, the promiscuity of the site rather than the drug mainly explains the multiple interactions between the drug and target, as most ligand types are dedicated to one site. This underlines the essential contribution of binding site promiscuity to drug promiscuity between different protein classes

Deep dive into the immune response against murine mesothelioma permits design of novel anti-mesothelioma therapeutics

International audienceGiven the need to improve the efficacy of standard-of-care immunotherapy (anti-CTLA-4 + anti-PD-1) in human malignant pleural mesothelioma (hMPM), we thoroughly characterized the immunobiology of the AB12 murine mesothelioma (MM) model, aiming to increase its accuracy in predicting the response of hMPM to immunotherapy and in designing novel anti-hMPM treatments. Specifically, we used immunologic, transcriptomic and survival analyses, to synchronize the MM tumor growth phases and immune evolution with the histo-molecular and immunological characteristics of hMPM while also determining the anti-MM efficacy of standard-of-care anti-hMPM immunotherapy as a benchmark that novel therapeutics should meet. We report that early-, intermediate- and advanced- AB12 tumors are characterized by a bell-shaped anti-tumor response that peaks in intermediate tumors and decays in advanced tumors. We further show that intermediate- and advanced- tumors match with immune active (“hot”) and immune inactive (“cold”) hMPM respectively, and that they respond to immunotherapy in a manner that corresponds well with its performance in real-life settings. Finally, we show that in advanced tumors, addition of cisplatin to anti CTLA-4 + anti PD-1 can extend mice survival and invigorate the decaying anti-tumor response. Therefore, we highlight this triple combination as a worthy candidate to improve clinical outcomes in hMPM

Systemic AA Amyloidosis Caused by Inflammatory Hepatocellular Adenoma

International audienc