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1.
Proc Natl Acad Sci U S A ; 119(19): e2107006119, 2022 05 10.
Artículo en Inglés | MEDLINE | ID: mdl-35512098

RESUMEN

Cutaneous melanoma (CM) and uveal melanoma (UM) both originate from the melanocytic lineage but are primarily driven by distinct oncogenic drivers, BRAF/NRAS or GNAQ/GNA11, respectively. The melanocytic master transcriptional regulator, MITF, is essential for both CM development and maintenance, but its role in UM is largely unexplored. Here, we use zebrafish models to dissect the key UM oncogenic signaling events and establish the role of MITF in UM tumors. Using a melanocytic lineage expression system, we showed that patient-derived mutations of GNAQ (GNAQQ209L) or its upstream CYSLTR2 receptor (CYSLTR2L129Q) both drive UM when combined with a cooperating mutation, tp53M214K/M214K. The tumor-initiating potential of the major GNAQ/11 effector pathways, YAP, and phospholipase C-ß (PLCß)­ERK was also investigated in this system and thus showed that while activated YAP (YAPAA) induced UM with high potency, the patient-derived PLCß4 mutation (PLCB4D630Y) very rarely yielded UM tumors in the tp53M214K/M214K context. Remarkably, mitfa deficiency was profoundly UM promoting, dramatically accelerating the onset and progression of tumors induced by Tg(mitfa:GNAQQ209L);tp53M214K/M214K or Tg(mitfa:CYSLTR2L129Q);tp53M214K/M214K. Moreover, mitfa loss was sufficient to cooperate with GNAQQ209L to drive tp53­wild type UM development and allowed Tg(mitfa:PLCB4D630Y);tp53M214K/M214K melanocyte lineage cells to readily form tumors. Notably, all of the mitfa−/− UM tumors, including those arising in Tg(mitfa:PLCB4D630Y);tp53M214K/M214K;mitfa−/− zebrafish, displayed nuclear YAP while lacking hyperactive ERK indicative of PLCß signaling. Collectively, these data show that YAP signaling is the major mediator of UM and that MITF acts as a bona fide tumor suppressor in UM in direct opposition to its essential role in CM.


Asunto(s)
Melanoma , Neoplasias Cutáneas , Neoplasias de la Úvea , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/genética , Humanos , Melanoma/patología , Factor de Transcripción Asociado a Microftalmía/genética , Neoplasias de la Úvea/genética , Neoplasias de la Úvea/patología , Neoplasias de la Úvea/terapia , Melanoma Cutáneo Maligno
2.
Biochem Biophys Res Commun ; 520(2): 284-290, 2019 12 03.
Artículo en Inglés | MEDLINE | ID: mdl-31590918

RESUMEN

The Mesp1 lineage contributes to cardiac, hematopoietic and skeletal myogenic development. Interestingly, muscle stem cells residing in craniofacial skeletal muscles primarily arise from Mesp1+ progenitors, but those in trunk and limb skeletal muscles do not. To gain insights into the difference between the head and trunk/limb muscle developmental processes, we studied Mesp1+ skeletal myogenic derivatives via single-cell RNA-seq and other strategies. Using a doxycycline-inducible Mesp1-expressing mouse embryonic stem cell line, we found that the development of Mesp1-induced skeletal myogenic progenitors can be characterized by dynamic expression of PDGFRα and VCAM1. Single-cell RNA-seq analysis further revealed the heterogeneous nature of these Mesp1+ derivatives, spanning pluripotent and mesodermal to mesenchymal and skeletal myogenic. We subsequently reconstructed the single-cell trajectories of these subpopulations. Our data thereby provide a cell fate projection of Mesp1-induced skeletal myogenesis.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Músculo Esquelético/metabolismo , RNA-Seq , Análisis de la Célula Individual , Animales , Antibacterianos/farmacología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Doxiciclina/farmacología , Ratones , Desarrollo de Músculos/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos
3.
Pigment Cell Melanoma Res ; 35(5): 539-547, 2022 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-35869673

RESUMEN

Uveal melanoma (UM) is the most common primary malignancy of the adult eye but lacks any FDA-approved therapy for the deadly metastatic disease. Thus, there is a great need to dissect the driving mechanisms for UM and develop strategies to evaluate potential therapeutics. Using an autochthonous zebrafish model, we previously identified MITF, the master melanocyte transcription factor, as a tumor suppressor in GNAQQ209L -driven UM. Here, we show that zebrafish mitfa-deficient GNAQQ209L -driven tumors significantly up-regulate neural crest markers, and that higher expression of a melanoma-associated neural crest signature correlates with poor UM patient survival. We further determined how the mitfa-null state, as well as expression of GNAQQ209L , YAPS127A;S381A , or BRAFV600E oncogenes, impacts melanocyte lineage cells before they acquire the transformed state. Specifically, examination 5 days post-fertilization showed that mitfa-deficiency is sufficient to up-regulate pigment progenitor and neural crest markers, while GNAQQ209L expression promotes a proliferative phenotype that is further enhanced by YAPS127A;S381A co-expression. Finally, we show that this oncogene-induced proliferative phenotype can be used to screen chemical inhibitors for their efficacy against the UM pathway. Overall, this study establishes that a neural crest signature correlates with poor UM survival, and describes an in vivo assay for preclinical trials of potential UM therapeutics.


Asunto(s)
Factor de Transcripción Asociado a Microftalmía/metabolismo , Neoplasias de la Úvea , Pez Cebra , Animales , Linaje de la Célula , Proliferación Celular , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/genética , Melanocitos/metabolismo , Melanoma , Mutación , Oncogenes , Neoplasias de la Úvea/patología , Pez Cebra/genética
4.
Pigment Cell Melanoma Res ; 31(5): 604-613, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-29570931

RESUMEN

Uveal melanoma (UM) is the most common primary intraocular cancer and has a high incidence of metastasis, which lacks any effective treatment. Here, we present zebrafish models of UM, which are driven by melanocyte-specific expression of activating GNAQ or GNA11 alleles, GNAQ/11Q209L , the predominant initiating mutations for human UM. When combined with mutant tp53, GNAQ/11Q209L transgenics develop various melanocytic tumors, including UM, with near complete penetrance. These tumors display nuclear YAP localization and thus phenocopy human UM. We show that GNAQ/11Q209L expression induces profound melanocyte defects independent of tp53 mutation, which are apparent within 3 days of development. First, increases in melanocyte number, melanin content, and subcellular melanin distribution result in hyperpigmentation. Additionally, altered melanocyte migration, survival properties, and evasion of normal boundary cues lead to aberrant melanocyte localization and stripe patterning. Collectively, these data show that GNAQ/11Q209L is sufficient to induce numerous protumorigenic changes within melanocytes.


Asunto(s)
Subunidades alfa de la Proteína de Unión al GTP Gq-G11/genética , Subunidades alfa de la Proteína de Unión al GTP/genética , Hiperpigmentación/patología , Melanocitos/patología , Melanoma/patología , Mutación , Lesiones Precancerosas/patología , Neoplasias de la Úvea/patología , Animales , Animales Modificados Genéticamente/genética , Animales Modificados Genéticamente/crecimiento & desarrollo , Células Cultivadas , Humanos , Hiperpigmentación/genética , Melanocitos/metabolismo , Melanoma/genética , Lesiones Precancerosas/genética , Neoplasias de la Úvea/genética , Pez Cebra/genética , Pez Cebra/crecimiento & desarrollo
5.
Stem Cell Reports ; 6(1): 26-34, 2016 Jan 12.
Artículo en Inglés | MEDLINE | ID: mdl-26771351

RESUMEN

The branchiomeric skeletal muscles co-evolved with new chambers of the heart to enable predatory feeding in chordates. These co-evolved tissues develop from a common population in anterior splanchnic mesoderm, referred to as cardiopharyngeal mesoderm (CPM). The regulation and development of CPM are poorly understood. We describe an embryonic stem cell-based system in which MESP1 drives a PDGFRA+ population with dual cardiac and skeletal muscle differentiation potential, and gene expression resembling CPM. Using this system, we investigate the regulation of these bipotent progenitors, and find that cardiac specification is governed by an antagonistic TGFß-BMP axis, while skeletal muscle specification is enhanced by Rho kinase inhibition. We define transcriptional signatures of the first committed CPM-derived cardiac and skeletal myogenic progenitors, and discover surface markers to distinguish cardiac (PODXL+) from the skeletal muscle (CDH4+) CPM derivatives. These tools open an accessible window on this developmentally and evolutionarily important population.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Mesodermo/metabolismo , Desarrollo de Músculos/genética , Músculo Esquelético/metabolismo , Miocardio/metabolismo , Células Madre Pluripotentes/metabolismo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Cadherinas/genética , Cadherinas/metabolismo , Diferenciación Celular/genética , Células Cultivadas , Perfilación de la Expresión Génica/métodos , Regulación del Desarrollo de la Expresión Génica , Inmunohistoquímica , Mesodermo/citología , Ratones , Células Madre Embrionarias de Ratones/citología , Células Madre Embrionarias de Ratones/metabolismo , Músculo Esquelético/citología , Miocardio/citología , Células Madre Pluripotentes/citología , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sialoglicoproteínas/genética , Sialoglicoproteínas/metabolismo
6.
Cell Stem Cell ; 12(5): 587-601, 2013 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-23642367

RESUMEN

Mesp1 is regarded as the master regulator of cardiovascular development, initiating the cardiac transcription factor cascade to direct the generation of cardiac mesoderm. To define the early embryonic cell population that responds to Mesp1, we performed pulse inductions of gene expression over tight temporal windows following embryonic stem cell differentiation. Remarkably, instead of promoting cardiac differentiation in the initial wave of mesoderm, Mesp1 binds to the Tal1 (Scl) +40 kb enhancer and generates Flk-1+ precursors expressing Etv2 (ER71) and Tal1 that undergo hematopoietic differentiation. The second wave of mesoderm responds to Mesp1 by differentiating into PDGFRα+ precursors that undergo cardiac differentiation. Furthermore, in the absence of serum-derived factors, Mesp1 promotes skeletal myogenic differentiation. Lineage tracing revealed that the majority of yolk sac and many adult hematopoietic cells derive from Mesp1+ precursors. Thus, Mesp1 is a context-dependent determination factor, integrating the stage of differentiation and the signaling environment to specify different lineage outcomes.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Tipificación del Cuerpo , Corazón/embriología , Sistema Hematopoyético/embriología , Mesodermo/embriología , Músculo Esquelético/embriología , Células Madre/citología , Envejecimiento/metabolismo , Animales , Emparejamiento Base/genética , Células de la Médula Ósea/citología , Diferenciación Celular , Embrión de Mamíferos/citología , Embrión de Mamíferos/metabolismo , Elementos de Facilitación Genéticos/genética , Hematopoyesis , Sistema Hematopoyético/citología , Mesodermo/citología , Mesodermo/metabolismo , Ratones , Ratones Endogámicos mdx , Desarrollo de Músculos , Músculo Esquelético/patología , Miocitos Cardíacos/citología , Miocitos Cardíacos/metabolismo , Unión Proteica , Multimerización de Proteína , Proteínas Proto-Oncogénicas/metabolismo , Células Satélite del Músculo Esquelético/metabolismo , Células Satélite del Músculo Esquelético/patología , Células Madre/metabolismo , Proteína 1 de la Leucemia Linfocítica T Aguda , Factores de Tiempo , Factores de Transcripción/metabolismo , Saco Vitelino/metabolismo
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