Genetic and pharmacological targeting of activin receptor-like kinase 1 impairs tumor growth and angiogenesis

Members of the transforming growth factor β (TGF-β) family have been genetically linked to vascular formation during embryogenesis. However, contradictory studies about the role of TGF-β and other family members with reported vascular functions, such as bone morphogenetic protein (BMP) 9, in physiological and pathological angiogenesis make the need for mechanistic studies apparent. We demonstrate, by genetic and pharmacological means, that the TGF-β and BMP9 receptor activin receptor-like kinase (ALK) 1 represents a new therapeutic target for tumor angiogenesis. Diminution of ALK1 gene dosage or systemic treatment with the ALK1-Fc fusion protein RAP-041 retarded tumor growth and progression by inhibition of angiogenesis in a transgenic mouse model of multistep tumorigenesis. Furthermore, RAP-041 significantly impaired the in vitro and in vivo angiogenic response toward vascular endothelial growth factor A and basic fibroblast growth factor. In seeking the mechanism for the observed effects, we uncovered an unexpected signaling synergy between TGF-β and BMP9, through which the combined action of the two factors augmented the endothelial cell response to angiogenic stimuli. We delineate a decisive role for signaling by TGF-β family members in tumor angiogenesis and offer mechanistic insight for the forthcoming clinical development of drugs blocking ALK1 in oncology

Clinical presentation and proteomic signature of patients with TANGO2 mutations

Transport And Golgi Organization protein 2 (TANGO2) deficiency has recently been identified as a rare metabolic disorder with a distinct clinical and biochemical phenotype of recurrent metabolic crises, hypoglycemia, lactic acidosis, rhabdomyolysis, arrhythmias, and encephalopathy with cognitive decline. We report nine subjects from seven independent families, and we studied muscle histology, respiratory chain enzyme activities in skeletal muscle and proteomic signature of fibroblasts. All nine subjects carried autosomal recessive TANGO2 mutations. Two carried the reported deletion of exons 3 to 9, one homozygous, one heterozygous with a 22q11.21 microdeletion inherited in trans. The other subjects carried three novel homozygous (c.262C&gt;T/p.Arg88*; c.220A&gt;C/p.Thr74Pro; c.380+1G&gt;A), and two further novel heterozygous (c.6_9del/p.Phe6del); c.11-13delTCT/p.Phe5del mutations. Immunoblot analysis detected a significant decrease of TANGO2 protein. Muscle histology showed mild variation of fiber diameter, no ragged-red/cytochrome c oxidase-negative fibers and a defect of multiple respiratory chain enzymes and coenzyme Q10 (CoQ10 ) in two cases, suggesting a possible secondary defect of oxidative phosphorylation. Proteomic analysis in fibroblasts revealed significant changes in components of the mitochondrial fatty acid oxidation, plasma membrane, endoplasmic reticulum-Golgi network and secretory pathways. Clinical presentation of TANGO2 mutations is homogeneous and clinically recognizable. The hemizygous mutations in two patients suggest that some mutations leading to allele loss are difficult to detect. A combined defect of the respiratory chain enzymes and CoQ10 with altered levels of several membrane proteins provides molecular insights into the underlying pathophysiology and may guide rational new therapeutic interventions.</p

Deficiency for endoglin in tumor vasculature weakens the endothelial barrier to metastatic dissemination

Therapy-induced resistance remains a significant hurdle to achieve long-lasting responses and cures in cancer patients. We investigated the long-term consequences of genetically impaired angiogenesis by engineering multiple tumor models deprived of endoglin, a co-receptor for TGF-β in endothelial cells actively engaged in angiogenesis. Tumors from endoglin-deficient mice adapted to the weakened angiogenic response, and refractoriness to diminished endoglin signaling was accompanied by increased metastatic capability. Mechanistic studies in multiple mouse models of cancer revealed that deficiency for endoglin resulted in a tumor vasculature that displayed hallmarks of endothelial-to-mesenchymal transition, a process of previously unknown significance in cancer biology, but shown by us to be associated with a reduced capacity of the vasculature to avert tumor cell intra- and extravasation. Nevertheless, tumors deprived of endoglin exhibited a delayed onset of resistance to anti-VEGF (vascular endothelial growth factor) agents, illustrating the therapeutic utility of combinatorial targeting of multiple angiogenic pathways for the treatment of cancer

Interaction between salt tectonic and sedimentation within salt-related mini-basins : the case of the Oligo-Miocene formations in the Sivas Basin, Turkey

L’objectif de cette thèse est d’analyser l’évolution d’une province à mini-bassins salifères, en s’appuyant sur l’étude des variations spatiales et temporelles de faciès, d’épaisseurs ainsi que des géométries développées lors du fluage des évaporites. L’exemple naturel investigué est le bassin de Sivas, situé sur le Plateau central Anatolien en Turquie. Ce bassin d’avant-pays enregistre à l’Oligo-Miocène la formation de nombreux mini-bassins secondaires au-dessus d’un niveau d’évaporites allochtones. A partir d’une cartographie et d’une description détaillées des séries sédimentaires accumulées dans les mini-bassins de Sivas, nous avons pu identifier trois ensembles tectono-sédimentaires cohérents :• la formation Karayün (Oligocène moyen à supérieur), constituée de dépôts de playa-lake, fluviatile en tresse et fluvio-lacustre, interprétée comme proche d’un système fluviatile en distributaires ;• la formation Karacaören (Oligocène supérieur, Miocène inférieur), interprétée comme une série alternante entre une rampe mixte deltaïque et carbonatée, et des dépôts de lagune et de plaine côtière ;• la formation de Benlikaya (Miocène), constituée de dépôts de cônes alluviaux, fluviatiles en tresse et playa-lake, interprétée également comme proche d’un système fluviatile en distributaires.Malgré de nombreuses variations de l’épaisseur et de la succession sédimentaire inter- et intra-bassins, des unités stratigraphiques équivalentes ont pu être déterminées à partir de l’identification de lignes isochrones marquant des changements de tendances. Nous avons montré alors que le système sédimentaire de chacun des mini-bassins est contrôlé au premier ordre par trois facteurs interdépendants, à savoir :• l’accommodation par halocinèse, provoquant la surrection des diapirs et des murs périphériques lors de la subsidence du mini-bassin. Ce fluage des évaporites produit des variations intra-basinales de faciès et d’épaisseurs, associées à des déformations syn-sédimentaires en bordure de mini-bassins. À plus grande échelle, ces objets salifères produisent une compartimentation inter-bassins des environnements de dépôts.• le taux d’accumulation sédimentaire, qui influence la faciologie et l’architecture stratigraphique des dépôts.• l’accommodation régionale, lié à la flexure du bassin, à l’origine du dépôt de série isopaques pouvant recouvrir les diapirs et finalement masquer l’influence salifère.À ces paramètres communs aux provinces salifères, nous ajoutons, l’influence des contraintes tectoniques compressives qui modifient les rétroactions entres ces facteurs.The aim of this thesis is to investigate the development of a salt-related mini-basin province, based on spatial and temporal changes in the facies assemblages, stratigraphic architecture and thicknesses, as well as stratal structures related to salt movement. The study area is the Sivas Basin, located in the Central Anatolian Plateau of Turkey, which is a foreland basin that records the formation during the Oligo-Miocene of numerous secondary mini-basins on top of an allochthonous evaporite canopy. Through detailed mapping of the Sivas mini-basin province, we provide a new and comprehensive description of the stratigraphic vertical succession including:• the Karayün Fm (Mid to upper Oligocene), comprising playa-lake, fluvial braided and fluvio-lacustrine deposits, and interpreted as a large distributive fluvial system;• the Karacaören Fm (Up. Oligocene to Low. Miocene), comprising two main sub-environments: mixed deltaic and carbonate ramp, alternating with coastal plain and restricted lagoon;• the Benlikaya Fm (Miocene), comprising alluvial fan, fluvial braided and playa-lake deposits interpreted also as a large distributive fluvial system;Within neighbouring minibasins and despite a similar vertical stratigraphic succession, variations are observed in stratigraphic units of equivalent age within and between minibasins. At the first order, we have defined three factors that dictate the pattern of mini-basin filling:• salt-induced accommodation producing local faciologic and stratigraphic thickness changes, and halokinetic structures along mini-basin borders. At larger scale, salt structures result in a compartmentalization of facies between basins.• The sediment supply rate, which affects facies assemblage and stratigraphic architecture.• Tectonically driven regional accommodation attributed to the foreland flexure, inducing the deposition of relatively isopachous series draping and finally obscuring the salt topography.In addition, these three factors are largely influenced by shortening during the evolution of the Sivas fold-and-thrust-belt

Interaction entre la tectonique salifère et la sédimentation dans des mini-bassins : Exemple de l'Oligo-Miocène du bassin de Sivas, Turquie.

The aim of this thesis is to investigate the development of a salt-related mini-basin province, based on spatial and temporal changes in the facies assemblages, stratigraphic architecture and thicknesses, as well as stratal structures related to salt movement. The study area is the Sivas Basin, located in the Central Anatolian Plateau of Turkey, which is a foreland basin that records the formation during the Oligo-Miocene of numerous secondary mini-basins on top of an allochthonous evaporite canopy. Through detailed mapping of the Sivas mini-basin province, we provide a new and comprehensive description of the stratigraphic vertical succession including: - the Karayün Fm (Mid to upper Oligocene), comprising playa-lake, fluvial braided and fluvio-lacustrine deposits, and interpreted as a large distributive fluvial system; - the Karacaören Fm (Up. Oligocene to Low. Miocene), comprising two main sub-environments: mixed deltaic and carbonate ramp, alternating with coastal plain and restricted lagoon; - the Benlikaya Fm (Miocene), comprising alluvial fan, fluvial braided and playa-lake deposits interpreted also as a large distributive fluvial system; Within neighbouring minibasins and despite a similar vertical stratigraphic succession, variations are observed in stratigraphic units of equivalent age within and between minibasins. At the first order, we have defined three factors that dictate the pattern of mini-basin filling: - salt-induced accommodation producing local faciologic and stratigraphic thickness changes, and halokinetic structures along mini-basin borders. At larger scale, salt structures result in a compartmentalization of facies between basins. - The sediment supply rate, which affects facies assemblage and stratigraphic architecture. -Tectonically driven regional accommodation attributed to the foreland flexure, inducing the deposition of relatively isopachous series draping and finally obscuring the salt topography. In addition, this three factors are largely influenced by shortening during the evolution of the Sivas fold-and-thrust-belt.L’objectif de cette thèse est d’analyser l’évolution d’une province à mini-bassins salifères, en s’appuyant sur l’étude des variations spatiales et temporelles de faciès, d’épaisseurs ainsi que des géométries développées lors du fluage des évaporites. L’exemple naturel investigué est le bassin de Sivas, situé sur le Plateau central Anatolien en Turquie. Ce bassin d’avant-pays enregistre à l’Oligo-Miocène la formation de nombreux mini-bassins secondaires au-dessus d’un niveau d’évaporites allochtones. A partir d’une cartographie et d’une description détaillées des séries sédimentaires accumulées dans les mini-bassins de Sivas, nous avons pu identifier trois ensembles tectono- sédimentaires cohérents : -la formation Karayün (Oligocène moyen à supérieur), constituée de dépôts de playa-lake, fluviatile en tresse et fluvio-lacustre, interprétée comme proche d’un système fluviatile en distributaires ; -la formation Karacaören (Oligocène supérieur, Miocène inférieur), interprétée comme une série alternante entre une rampe mixte deltaïque et carbonatée, et des dépôts de lagune et de plaine côtière ; -la formation de Benlikaya (Miocène), constituée de dépôts de cônes alluviaux, fluviatiles en tresse et playa- lake, interprétée également comme proche d’un système fluviatile en distributaires. Malgré de nombreuses variations de l’épaisseur et de la succession sédimentaire inter- et intra-bassins, des unités stratigraphiques équivalentes ont pu être déterminées à partir de l’identification de lignes isochrones marquant des changements de tendances. Nous avons montré alors que le système sédimentaire de chacun des mini-bassins est contrôlé au premier ordre par trois facteurs interdépendants, à savoir : - l’accommodation par halocinèse, provoquant la surrection des diapirs et des murs périphériques lors de la subsidence du mini-bassin. Ce fluage des évaporites produit des variations intra-basinales de faciès et d’épaisseurs, associées à des déformations syn-sédimentaires en bordure de mini-bassins. À plus grande échelle, ces objets salifères produisent une compartimentation inter-bassins des environnements de dépôts. -le taux d’accumulation sédimentaire, qui influence la faciologie et l’architecture stratigraphique des dépôts. -l’accommodation régionale, lié à la flexure du bassin, à l’origine du dépôt de sérieS isopaques pouvant recouvrir les diapirs et finalement masquer l’influence salifère.À ces paramètres communs aux provinces salifères, nous ajoutons, l’influence des contraintes tectoniques compressives qui modifient les rétroactions entres ces facteurs

Fluid circulations associated with the necking of the crust: the example of the Mont-Blanc detachment fault

International audienc

Fluid circulations associated with the necking of the crust: the example of the Mont-Blanc detachment fault

International audienc

The syn‐rift tectono‐stratigraphic record of rifted margins (Part I): Insights from the Alpine Tethys

International audienceThe tectono-stratigraphic evolution of rift systems is at present poorly understood, especially the one preceding the onset of oceanic seafloor spreading. Improving our understanding of the complex, polyphase tectonic evolution of the fossil Alpine Tethys, one of the best calibrated magma-poor rift systems worldwide, offers great potential for the interpretation of the distal part of global rifted margins, which notoriously lack data. In this paper, we propose a tectonostratigraphic model for the former Alpine Tethys, whose remnants are exposed in the Alps of Western Europe. We fist review the historical evolution of some concepts grounding present knowledge on the Alpine-and global magma-poor rifted margins. Then we present a spatial and temporal template for the Alpine Tethys rift system using a "building block (BB)" approach. This new approach is powerful in that it can integrate high-resolution, structural, stratigraphic, thermochronological and petrological observations from dismembered outcrops into a margin-scale template compatible with the first-order seismic architecture defined at present-day, magma-poor rifted margins. The detailed analysis of the syn-rift sequence of the Alpine Tethys margins demonstrates that extension migrated and localized while evolving from the stretching to the necking phase. During hyperextension, rifting was asymmetric and controlled by in-sequence detachment faulting. Then, the rift system evolved back into a more symmetric, embryonic spreading system. With this contribution, we aim to allow readers without knowledge of the Alps to access to this unique "archive" preserving some of the world's best-exposed rift structures. Recognising these structures is critical to understand the origin of some new concepts used to explain present-day, deep-water rifted margins, and to interpret and predict the tectono-stratigraphic evolution during advanced stages of rifting. Highlights: Our "building block" approach enables us to upscale local outcrop observations into a global margin template The syn-rift sequence of the Alpine Tethys margins is among the best calibrated worldwide The observed rift migration-localization has far-reaching consequences for the interpretation of global rifted margin

Reply to comment on "Structural and petrological characteristics of a Jurassic detachment fault from the Mont-Blanc massif (Col du Bonhomme area, France)" (Journal of Structural Geology, 159 (2022))

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