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1.
Oncogene ; 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31616059

RESUMO

Targeting Notch signaling has emerged as a promising therapeutic strategy for chronic lymphocytic leukemia (CLL), particularly in NOTCH1-mutated patients. We provide first evidence that the Notch ligand DLL4 is a potent stimulator of Notch signaling in NOTCH1-mutated CLL cells while increases cell proliferation. Importantly, DLL4 is expressed in histiocytes from the lymph node, both in NOTCH1-mutated and -unmutated cases. We also show that the DLL4-induced activation of the Notch signaling pathway can be efficiently blocked with the specific anti-Notch1 antibody OMP-52M51. Accordingly, OMP-52M51 also reverses Notch-induced MYC, CCND1, and NPM1 gene expression as well as cell proliferation in NOTCH1-mutated CLL cells. In addition, DLL4 stimulation triggers the expression of protumor target genes, such as CXCR4, NRARP, and VEGFA, together with an increase in cell migration and angiogenesis. All these events can be antagonized by OMP-52M51. Collectively, our results emphasize the role of DLL4 stimulation in NOTCH1-mutated CLL and confirm the specific therapeutic targeting of Notch1 as a promising approach for this group of poor prognosis CLL patients.

2.
Cancers (Basel) ; 11(10)2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31623163

RESUMO

Therapies that prevent metastatic dissemination and tumor growth in secondary organs are severely lacking. A better understanding of the mechanisms that drive metastasis will lead to improved therapies that increase patient survival. Within a tumor, cancer cells are equipped with different phenotypic and functional capacities that can impact their ability to complete the metastatic cascade. That phenotypic heterogeneity can be derived from a combination of factors, in which the genetic make-up, interaction with the environment, and ability of cells to adapt to evolving microenvironments and mechanical forces play a major role. In this review, we discuss the specific properties of those cancer cell subgroups and the mechanisms that confer or restrict their capacity to metastasize.

3.
Cell Rep ; 28(10): 2491-2500.e5, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31484062

RESUMO

Cancer metastasis is a process whereby a primary tumor spreads to distant organs. We have demonstrated previously that blood flow controls the intravascular arrest of circulating tumor cells (CTCs) through stable adhesion to endothelial cells. We now aim to define the contribution of cell adhesion potential and identify adhesion receptors at play. Early arrest is mediated by the formation of weak adhesion, depending on CD44 and integrin αvß3. Stabilization of this arrest uses integrin α5ß1-dependent adhesions with higher adhesion strength, which allows CTCs to stop in vascular regions with lower shear forces. Moreover, blood flow favors luminal deposition of fibronectin on endothelial cells, an integrin α5ß1 ligand. Finally, we show that only receptors involved in stable adhesion are required for subsequent extravasation and metastasis. In conclusion, we identified the molecular partners that are sequentially exploited by CTCs to arrest and extravasate in vascular regions with permissive flow regimes.

4.
Dev Cell ; 48(4): 554-572.e7, 2019 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-30745140

RESUMO

Tumor extracellular vesicles (EVs) mediate the communication between tumor and stromal cells mostly to the benefit of tumor progression. Notably, tumor EVs travel in the bloodstream, reach distant organs, and locally modify the microenvironment. However, visualizing these events in vivo still faces major hurdles. Here, we describe an approach for tracking circulating tumor EVs in a living organism: we combine chemical and genetically encoded probes with the zebrafish embryo as an animal model. We provide a first description of tumor EVs' hemodynamic behavior and document their intravascular arrest. We show that circulating tumor EVs are rapidly taken up by endothelial cells and blood patrolling macrophages and subsequently stored in degradative compartments. Finally, we demonstrate that tumor EVs activate macrophages and promote metastatic outgrowth. Overall, our study proves the usefulness and prospects of zebrafish embryo to track tumor EVs and dissect their role in metastatic niches formation in vivo.


Assuntos
Células Endoteliais/citologia , Vesículas Extracelulares/metabolismo , Neoplasias/patologia , Microambiente Tumoral/fisiologia , Animais , Comunicação Celular/fisiologia , Modelos Animais de Doenças , Progressão da Doença , Exossomos/metabolismo , Células Estromais/metabolismo , Peixe-Zebra
5.
Development ; 145(16)2018 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-30042180

RESUMO

T-cell development is a complex dynamic process that relies on ordered stromal signals delivered to thymus-seeding progenitors that migrate throughout different thymus microenvironments (TMEs). Particularly, Notch signaling provided by thymic epithelial cells (TECs) is crucial for T-cell fate specification and generation of mature T cells. Four canonical Notch ligands (Dll1, Dll4, Jag1 and Jag2) are expressed in the thymus, but their spatial distribution in functional TMEs is largely unknown, especially in humans, and their impact on Notch1 activation during T-lymphopoiesis remains undefined. Based on immunohistochemistry and quantitative confocal microscopy of fetal, postnatal and adult human and mouse thymus samples, we show that spatial regulation of Notch ligand expression defines discrete Notch signaling niches and dynamic species-specific TMEs. We further show that Notch ligand expression, particularly DLL4, is tightly regulated in cortical TECs during human thymus ontogeny and involution. Also, we provide the first evidence that NOTCH1 activation is induced in vivo in CD34+ progenitors and developing thymocytes at particular cortical niches of the human fetal and postnatal thymus. Collectively, our results show that human thymopoiesis involves complex spatiotemporal regulation of Notch ligand expression, which ensures the coordinated delivery of niche-specific NOTCH1 signals required for dynamic T-cell development.


Assuntos
Receptor Notch1/metabolismo , Timo/crescimento & desenvolvimento , Timo/metabolismo , Adolescente , Adulto , Envelhecimento/metabolismo , Animais , Antígenos CD34/metabolismo , Criança , Feto/embriologia , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Lactente , Recém-Nascido , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Organogênese , Proteínas Serrate-Jagged/metabolismo , Transdução de Sinais , Células-Tronco/metabolismo , Células Estromais/citologia , Células Estromais/metabolismo , Timócitos/citologia , Timócitos/metabolismo , Timo/citologia , Timo/embriologia
6.
J Clin Invest ; 128(7): 2802-2818, 2018 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-29781813

RESUMO

NOTCH1 is a prevalent signaling pathway in T cell acute lymphoblastic leukemia (T-ALL), but crucial NOTCH1 downstream signals and target genes contributing to T-ALL pathogenesis cannot be retrospectively analyzed in patients and thus remain ill defined. This information is clinically relevant, as initiating lesions that lead to cell transformation and leukemia-initiating cell (LIC) activity are promising therapeutic targets against the major hurdle of T-ALL relapse. Here, we describe the generation in vivo of a human T cell leukemia that recapitulates T-ALL in patients, which arises de novo in immunodeficient mice reconstituted with human hematopoietic progenitors ectopically expressing active NOTCH1. This T-ALL model allowed us to identify CD44 as a direct NOTCH1 transcriptional target and to recognize CD44 overexpression as an early hallmark of preleukemic cells that engraft the BM and finally develop a clonal transplantable T-ALL that infiltrates lymphoid organs and brain. Notably, CD44 is shown to support crucial BM niche interactions necessary for LIC activity of human T-ALL xenografts and disease progression, highlighting the importance of the NOTCH1/CD44 axis in T-ALL pathogenesis. The observed therapeutic benefit of anti-CD44 antibody administration in xenotransplanted mice holds great promise for therapeutic purposes against T-ALL relapse.


Assuntos
Receptores de Hialuronatos/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/etiologia , Receptor Notch1/metabolismo , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Transplante de Células-Tronco Hematopoéticas , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Mutação , Transplante de Neoplasias , Leucemia-Linfoma Linfoblástico de Células T Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Receptor Notch1/genética , Transdução de Sinais
7.
J Exp Med ; 214(11): 3361-3379, 2017 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-28947612

RESUMO

A key unsolved question regarding the developmental origin of conventional and plasmacytoid dendritic cells (cDCs and pDCs, respectively) resident in the steady-state thymus is whether early thymic progenitors (ETPs) could escape T cell fate constraints imposed normally by a Notch-inductive microenvironment and undergo DC development. By modeling DC generation in bulk and clonal cultures, we show here that Jagged1 (JAG1)-mediated Notch signaling allows human ETPs to undertake a myeloid transcriptional program, resulting in GATA2-dependent generation of CD34+ CD123+ progenitors with restricted pDC, cDC, and monocyte potential, whereas Delta-like1 signaling down-regulates GATA2 and impairs myeloid development. Progressive commitment to the DC lineage also occurs intrathymically, as myeloid-primed CD123+ monocyte/DC and common DC progenitors, equivalent to those previously identified in the bone marrow, are resident in the normal human thymus. The identification of a discrete JAG1+ thymic medullary niche enriched for DC-lineage cells expressing Notch receptors further validates the human thymus as a DC-poietic organ, which provides selective microenvironments permissive for DC development.


Assuntos
Células Dendríticas/metabolismo , Proteína Jagged-1/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais , Nicho de Células-Tronco , Timo/metabolismo , Proteínas de Ligação ao Cálcio , Diferenciação Celular , Linhagem da Célula , Células Cultivadas , Fator de Transcrição GATA2/genética , Fator de Transcrição GATA2/metabolismo , Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Subunidade alfa de Receptor de Interleucina-3/metabolismo , Proteína Jagged-1/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Microscopia Confocal , Monócitos/citologia , Monócitos/metabolismo , Células Mieloides/citologia , Células Mieloides/metabolismo , Receptores Notch/genética , Linfócitos T/citologia , Linfócitos T/metabolismo , Timo/citologia
8.
Sci Rep ; 6: 20223, 2016 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-26838552

RESUMO

Evidence links aryl hydrocarbon receptor (AHR) activation to rheumatoid arthritis (RA) pathogenesis, although results are inconsistent. AHR agonists inhibit pro-inflammatory cytokine expression in macrophages, pivotal cells in RA aetiopathogenesis, which hints at specific circuits that regulate the AHR pathway in RA macrophages. We compared microRNA (miR) expression in CD14(+) cells from patients with active RA or with osteoarthritis (OA). Seven miR were downregulated and one (miR-223) upregulated in RA compared to OA cells. miR-223 upregulation correlated with reduced Notch3 and Notch effector expression in RA patients. Overexpression of the Notch-induced repressor HEY-1 and co-culture of healthy donor monocytes with Notch ligand-expressing cells showed direct Notch-mediated downregulation of miR-223. Bioinformatics predicted the AHR regulator ARNT (AHR nuclear translocator) as a miR-223 target. Pre-miR-223 overexpression silenced ARNT 3'UTR-driven reporter expression, reduced ARNT (but not AHR) protein levels and prevented AHR/ARNT-mediated inhibition of pro-inflammatory cytokine expression. miR-223 counteracted AHR/ARNT-induced Notch3 upregulation in monocytes. Levels of ARNT and of CYP1B1, an AHR/ARNT signalling effector, were reduced in RA compared to OA synovial tissue, which correlated with miR-223 levels. Our results associate Notch signalling to miR-223 downregulation in RA macrophages, and identify miR-223 as a negative regulator of the AHR/ARNT pathway through ARNT targeting.


Assuntos
Artrite Reumatoide/genética , Translocador Nuclear Receptor Aril Hidrocarboneto/metabolismo , Citocinas/metabolismo , Macrófagos/metabolismo , MicroRNAs/genética , Receptores Notch/genética , Idoso , Artrite Reumatoide/patologia , Translocador Nuclear Receptor Aril Hidrocarboneto/genética , Técnicas de Cocultura , Citocinas/genética , Feminino , Perfilação da Expressão Gênica/métodos , Células HEK293 , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite/genética , Osteoartrite/patologia , Transdução de Sinais
10.
Nat Cell Biol ; 17(3): 241-50, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25706235

RESUMO

Epithelial organs develop through tightly coordinated events of cell proliferation and differentiation in which endocytosis plays a major role. Despite recent advances, how endocytosis regulates the development of vertebrate organs is still unknown. Here we describe a mechanism that facilitates the apical availability of endosomal SNARE receptors for epithelial morphogenesis through the developmental upregulation of plasmolipin (pllp) in a highly endocytic segment of the zebrafish posterior midgut. The protein PLLP (Pllp in fish) recruits the clathrin adaptor EpsinR to sort the SNARE machinery of the endolysosomal pathway into the subapical compartment, which is a switch for polarized endocytosis. Furthermore, PLLP expression induces apical Crumbs internalization and the activation of the Notch signalling pathway, both crucial steps in the acquisition of cell polarity and differentiation of epithelial cells. We thus postulate that differential apical endosomal SNARE sorting is a mechanism that regulates epithelial patterning.


Assuntos
Endossomos/metabolismo , Células Epiteliais/metabolismo , Epitélio/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Lisossomos/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/genética , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Animais , Diferenciação Celular , Linhagem Celular , Polaridade Celular , Proliferação de Células , Embrião não Mamífero , Endocitose , Endossomos/ultraestrutura , Células Epiteliais/ultraestrutura , Epitélio/ultraestrutura , Túbulos Renais/metabolismo , Túbulos Renais/ultraestrutura , Lisossomos/ultraestrutura , Camundongos , Proteínas Proteolipídicas Associadas a Linfócitos e Mielina/genética , Proteínas Proteolipídicas Associadas a Linfócitos e Mielina/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Receptores Notch/genética , Receptores Notch/metabolismo , Proteínas SNARE/genética , Proteínas SNARE/metabolismo , Transdução de Sinais , Peixe-Zebra
11.
Nucleic Acids Res ; 43(2): 760-74, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25539926

RESUMO

Thymocyte differentiation is a complex process involving well-defined sequential developmental stages that ultimately result in the generation of mature T-cells. In this study, we analyzed DNA methylation and gene expression profiles at successive human thymus developmental stages. Gain and loss of methylation occurred during thymocyte differentiation, but DNA demethylation was much more frequent than de novo methylation and more strongly correlated with gene expression. These changes took place in CpG-poor regions and were closely associated with T-cell differentiation and TCR function. Up to 88 genes that encode transcriptional regulators, some of whose functions in T-cell development are as yet unknown, were differentially methylated during differentiation. Interestingly, no reversion of accumulated DNA methylation changes was observed as differentiation progressed, except in a very small subset of key genes (RAG1, RAG2, CD8A, PTCRA, etc.), indicating that methylation changes are mostly unique and irreversible events. Our study explores the contribution of DNA methylation to T-cell lymphopoiesis and provides a fine-scale map of differentially methylated regions associated with gene expression changes. These can lay the molecular foundations for a better interpretation of the regulatory networks driving human thymopoiesis.


Assuntos
Metilação de DNA , Regulação da Expressão Gênica , Receptores de Antígenos de Linfócitos T alfa-beta/análise , Linfócitos T/imunologia , Transcrição Genética , Diferenciação Celular/genética , Expressão Gênica , Humanos , Linfócitos T/citologia , Linfócitos T/metabolismo , Timócitos/citologia , Timo/citologia , Timo/imunologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
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