Immune and Genetic Signatures of Breast Carcinomas Triggering Anti-Yo–Associated Paraneoplastic Cerebellar Degeneration

International audienceBackground and Objectives Paraneoplastic cerebellar degeneration (PCD) with anti-Yo antibodies is a cancer-related autoimmune disease directed against neural antigens expressed by tumor cells. A putative trigger of the immune tolerance breakdown is genetic alteration of Yo antigens. We aimed to identify the tumors' genetic and immune specificities involved in Yo-PCD pathogenesis. Methods Using clinicopathologic data, immunofluorescence (IF) imaging, and whole-transcriptome analysis, 22 breast cancers (BCs) associated with Yo-PCD were characterized in terms of oncologic characteristics, genetic alteration of Yo antigens, differential gene expression profiles, and morphofunctional specificities of their in situ antitumor immunity by comparing them with matched control BCs. Results Yo-PCD BCs were invasive carcinoma of no special type, which early metastasized to lymph nodes. They overexpressed human epidermal growth factor receptor 2 (HER2) but were hormone receptor negative. All Yo-PCD BCs carried at least 1 genetic alteration (variation or gain in copy number) on CDR2L, encoding the main Yo antigen that was found aberrantly overexpressed in Yo-PCD BCs. Analysis of the differentially expressed genes found 615 upregulated and 54 downregulated genes in Yo-PCD BCs compared with HER2-driven control BCs without PCD. Ontology enrichment analysis found significantly upregulated adaptive immune response pathways in Yo-PCD BCs. IF imaging confirmed an intense immune infiltration with an overwhelming predominance of immunoglobulin G-plasma cells. Discussion These data confirm the role of genetic alterations of Yo antigens in triggering the immune tolerance breakdown but also outline a specific biomolecular profile in Yo-PCD BCs, suggesting a cancer-specific pathogenesis

The transition from Pyrenean shortening to Gulf of Lion rifting in Languedoc (South France) - A tectonic sedimentation analysis

International audienceThe Pyrenean orogen extended eastward, across the present-day Gulf of Lion margin. The late or post-orogenic dismantling of this orogen segment, contemporaneous with ongoing shortening in the Spanish Pyrénées, is still debated. Understanding the transition between the two geodynamic events requires to document the precise timing of the succession of the tectonic processes involved. We investigate the superposition of rifting structures over Pyrenean thrusts and folds in the onshore Languedoc. Compilation and reassessment of the regional chronostratigraphy, in the light of recent biostratigraphic dating and new mapping of Paleogene basins, lead to date the transition to the Priabonian. Tectonic-sedimentation relationship in the Eocene to Oligocene depocentres are analysed in surface exposures as well as in seismic reflection surveys. Bed-to bed mapping allowed us to: i) characterise an intermediate sequence of Priabonian age, bounded at the base and the top by unconformities; ii) evidence syn-depositional deformation within the Priabonian; iii) define the axes of Priabonian deformation. Interpretation of seismic reflection profiles, across the onshore basins covered by syn- and post-rift sequences, reveals the existence of an intermediate sequence displaying similar features, and that is correlated to the Priabonian. Syn-depositional deformation of some Priabonian basins correspond to extensional structure, whereas neighbouring, contemporaneous basins, reveal compressional deformation. The distribution of such apparently conflicting observations across the studied area provides evidence for left-lateral strike-slip deformation between two major regional faults (Cévennes and Nîmes faults). Left-lateral strike-slip along NE-trending faults accommodates E-W extension of the West European Rift (ECRIS) and part of the ongoing N-S shortening in the Central and Western Pyrénées. Priabonian clastic sedimentation and deformation in Languedoc witness the initial stages of the dismantling of the Languedoc-Provence Pyrénées, prior to Oligocene-Aquitanian back-arc rifting.L’orogène pyrénéen s’étendait vers l’est à l’emplacement actuel du Golfe du Lion. Contemporain de la poursuite de la compression dans les Pyrénées franco-espagnoles, le démantèlement tardi- ou post-orogénique de ce segment de l’orogène est encore mal compris. La compréhension de la transition entre l’orogénèse Pyrénéo-Provençale et le rifting du Golfe du Lion nécessite de préciser le calendrier des évènements ainsi que la succession des différents processus tectoniques mis en jeu. Nous analysons la superposition des structures du rifting sur les structures compressives Pyrénéennes exposées à terre, dans le Languedoc. Tout d’abord, nous compilons et révisons la chronostratigraphie régionale, à la lumière de datations postérieures à la publication des cartes au 1/50 000 du BRGM, et de la cartographie de plusieurs bassins paléogènes. Nous datons cette transition du Priabonien. Nous analysons les relations tectonique-sédimentation des dépocentres Eocène à Oligocène sur le terrain et en sismique réflexion. La cartographie banc-par-banc permet de : i) caractériser une séquence intermédiaire d’âge Priabonien encadrée par deux discordances, ii) mettre en évidence une déformation syn-dépôt dans le remplissage Priabonien, iii) définir les axes de la déformation priabonienne. L’interprétation de profils de sismique réflexion à travers les bassins paléogènes à terre, recouverts par les séries syn- et post-rift, révèle l’existence d’une séquence intermédiaire présentant des caractéristiques similaires et que nous corrélons avec le Priabonien. La déformation syn-dépôt de certains bassins est extensive, alors que dans des bassins voisins contemporains, elle est compressive. La distribution régionale de ces observations apparemment contradictoires est interprétée comme liée à un couloir de déformation en décrochement senestre entre les failles majeures des Cévennes et de Nîmes, d’orientation NE-SW. Ce décrochement accommode l’extension EW des rifts ouest-européens et contribue au raccourcissement N-S des Pyrénées franco-espagnoles, toujours actif au Priabonien. La sédimentation syn-tectonique clastique du Priabonien du Languedoc enregistre les premiers stades du démantèlement de la chaîne pyrénéo-provençale, plusieurs millions d’années avant l’initiation de l’extension d’arrière-arc

Regulation of Tissue Factor by CD44 Supports Coagulant Activity in Breast Tumor Cells

International audiencePrevious work identified Tissue Factor (TF), a key activator of the coagulation cascade, as a gene induced in cellular contexts of Epithelial-Mesenchymal Transitions (EMTs), providing EMT+ Circulating Tumor Cells (CTCs) with coagulant properties that facilitate their metastatic seeding. Deciphering further molecular aspects of TF regulation in tumor cells, we report here that CD44 and TF coexpress in EMT contexts, and that CD44 acts as a regulator of TF expression supporting procoagulant properties and metastatic seeding. A transcriptional regulatory mechanism bridging CD44 to TF expression was further evidenced. Comparing different TF –promoter luciferase reporter constructs, we indeed found that the shortest -111 pb TF promoter fragment harboring three Specificity Protein 1 (Sp1) binding sites is still responsive to CD44 silencing. The observation that (i) mutation within Sp1 binding sites decreased the basal activity of the -111 pb TF promoter construct, (ii) CD44 silencing decreased Sp1 protein and mRNA levels and (iii) Sp1 silencing diminished TF expression further points to Sp1 as a key mediator linking CD44 to TF regulation. All together, these data thus report a transcriptional regulatory mechanism of TF expression by CD44 supporting procoagulant activity and metastatic competence of CTCs

Structural differences in the hippocampus and amygdala of behaviorally inhibited macaque monkeys

Behavioral inhibition is a temperamental disposition to react warily when confronted by unfamiliar people, objects, or events. Behaviorally inhibited children are at greater risk of developing anxiety disorders later in life. Previous studies reported that individuals with a history of childhood behavioral inhibition exhibit abnormal activity in the hippocampus and amygdala. However, few studies have investigated the structural differences that may underlie these functional abnormalities. In this exploratory study, we evaluated rhesus monkeys exhibiting a phenotype consistent with human behavioral inhibition. We performed quantitative neuroanatomical analyses that cannot be performed in humans including estimates of the volume and neuron number of distinct hippocampal regions and amygdala nuclei in behaviorally inhibited and control rhesus monkeys. Behaviorally inhibited monkeys had larger volumes of the rostral third of the hippocampal field CA3, smaller volumes of the rostral third of CA2, and smaller volumes of the accessory basal nucleus of the amygdala. Furthermore, behaviorally inhibited monkeys had fewer neurons in the rostral third of CA2. These structural differences may contribute to the functional abnormalities in the hippocampus and amygdala of behaviorally inhibited individuals. These structural findings in monkeys are consistent with a reduced modulation of amygdala activity via prefrontal cortex projections to the accessory basal nucleus. Given the putative roles of the amygdala in affective processing, CA3 in associative learning and CA2 in social memory, increased amygdala and CA3 activity, and diminished CA2 structure and function, may be associated with increased social anxiety and the heritability of behavioral inhibition. The findings from this exploratory study compel follow-up investigations with larger sample sizes and additional analyses to provide greater insight and more definitive answers regarding the neurobiological bases of behavioral inhibition

Structural differences in the hippocampus and amygdala of behaviorally inhibited macaque monkeys.

Behavioral inhibition is a temperamental disposition to react warily when confronted by unfamiliar people, objects, or events. Behaviorally inhibited children are at greater risk of developing anxiety disorders later in life. Previous studies reported that individuals with a history of childhood behavioral inhibition exhibit abnormal activity in the hippocampus and amygdala. However, few studies have investigated the structural differences that may underlie these functional abnormalities. In this exploratory study, we evaluated rhesus monkeys exhibiting a phenotype consistent with human behavioral inhibition. We performed quantitative neuroanatomical analyses that cannot be performed in humans including estimates of the volume and neuron number of distinct hippocampal regions and amygdala nuclei in behaviorally inhibited and control rhesus monkeys. Behaviorally inhibited monkeys had larger volumes of the rostral third of the hippocampal field CA3, smaller volumes of the rostral third of CA2, and smaller volumes of the accessory basal nucleus of the amygdala. Furthermore, behaviorally inhibited monkeys had fewer neurons in the rostral third of CA2. These structural differences may contribute to the functional abnormalities in the hippocampus and amygdala of behaviorally inhibited individuals. These structural findings in monkeys are consistent with a reduced modulation of amygdala activity via prefrontal cortex projections to the accessory basal nucleus. Given the putative roles of the amygdala in affective processing, CA3 in associative learning and CA2 in social memory, increased amygdala and CA3 activity, and diminished CA2 structure and function, may be associated with increased social anxiety and the heritability of behavioral inhibition. The findings from this exploratory study compel follow-up investigations with larger sample sizes and additional analyses to provide greater insight and more definitive answers regarding the neurobiological bases of behavioral inhibition

Regulation of Tissue Factor by CD44 supports coagulant activity in breast tumor cells.

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