Hippo-Independent Activation of YAP by the GNAQ Uveal Melanoma Oncogene through a Trio-Regulated Rho GTPase Signaling Circuitry

SummaryMutually exclusive activating mutations in the GNAQ and GNA11 oncogenes, encoding heterotrimeric Gαq family members, have been identified in ∼83% and ∼6% of uveal and skin melanomas, respectively. However, the molecular events underlying these GNAQ-driven malignancies are not yet defined, thus limiting the ability to develop cancer-targeted therapies. Here, we focused on the transcriptional coactivator YAP, a critical component of the Hippo signaling pathway that controls organ size. We found that Gαq stimulates YAP through a Trio-Rho/Rac signaling circuitry promoting actin polymerization, independently of phospholipase Cβ and the canonical Hippo pathway. Furthermore, we show that Gαq promotes the YAP-dependent growth of uveal melanoma cells, thereby identifying YAP as a suitable therapeutic target in uveal melanoma, a GNAQ/GNA11-initiated human malignancy

Adaptación de las asignaturas básicas de primer curso de la ETSI Navales de la UPM: Actividades 2008-2009

En el marco de la reforma de las titulaciones con motivo del Espacio Europeo de Educación un grupo de profesores hemos coordinado, durante el curso 2008-2009, todas las asignaturas básicas de primer curso y una más de segundo curso en la Escuela Técnica Superior de Ingenieros Navales. Las actividades realizadas son: a) Coordinación de todas las asignaturas básicas de primer curso, con reuniones periódicas de coordinación horizontal y el establecimiento de una página web de moodle para profesores como espacio para el trabajo cooperativo. Particularmente importante es el establecimiento de un calendario conjunto de pruebas de evaluación continua. b) Redacción de guías de aprendizaje, con un formato común para todas las asignaturas, incluyendo los objetivos formativos, los contenidos, las actividades formativas, los enlaces y la bibliografía. c) Establecimiento de una plataforma de teleeducación común para todas las asignaturas, uno de los objetivos fundamentales del proyecto, ya que coexistían dos plataformas distintas. Igualmente importante ha sido reforzar los contenidos y las actividades que se podían realizar en la plataforma. d) Seguimiento del tiempo dedicado por los alumnos, hemos ido siguiendo el tiempo dedicado por los alumnos a las distintas asignaturas, para detectar si el tiempo que se dedica está en los márgenes establecidos en los créditos ECTS. Igualmente, hemos hecho dos encuestas a la mitad de cada semestre, para recoger las opiniones de los alumnos sobre las asignaturas y sobre los aspectos relevantes del proyecto. e) Organización de actividades de nivelación, para los alumnos de nuevo ingreso, con la organización de cursos cero y la participación y coordinación en la Plataforma de Punto de inicio de la UPM. f) Organización de actividades formativas, para poder llevar a cabo estas tareas, hemos organizado, en colaboración con el Centro y el Gabinete de Tele-Educación (GATE) actividades formativas relacionadas con la plataforma moodle, métodos de evaluación y de formación en competencias.En la presentación haremos una descripción de las actividades realizadas, así como una primera evaluación de las mismas. Por último, describiremos las tareas a desarrollar en los próximos cursos

Phenotypic plasticity and epithelial-to-mesenchymal transition in the behaviour and therapeutic response of oral squamous cell carcinoma

This work was supported by the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs), by BAOMS/Saving Faces – FSRF, and by The Barts and The London Charity

The PI3K/Akt/mTOR axis in head and neck cancer: functions, aberrations, cross‐talk, and therapies

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/113753/1/odi12206.pd

Senolytics and senostatics as adjuvant tumour therapy

Cell senescence is a driver of ageing, frailty, age-associated disease and functional decline. In oncology, tumour cell senescence may contribute to the effect of adjuvant therapies, as it blocks tumour growth. However, this is frequently incomplete, and tumour cells that recover from senescence may gain a more stem-like state with increased proliferative potential. This might be exaggerated by the induction of senescence in the surrounding niche cells. Finally, senescence will spread through bystander effects, possibly overwhelming the capacity of the immune system to ablate senescent cells. This induces a persistent system-wide senescent cell accumulation, which we hypothesize is the cause for the premature frailty, multi-morbidity and increased mortality in cancer survivors. Senolytics, drugs that selectively kill senescent cells, have been developed recently and have been proposed as second-line adjuvant tumour therapy. Similarly, by blocking accelerated senescence following therapy, senolytics might prevent and potentially even revert premature frailty in cancer survivors. Adjuvant senostatic interventions, which suppress senescence-associated bystander signalling, might also have therapeutic potential. This becomes pertinent because treatments that are senostatic in vitro (e.g. dietary restriction mimetics) persistently reduce numbers of senescent cells in vivo, i.e. act as net senolytics in immunocompetent hosts

Unleashing Immunotherapy by Targeting Cancer Stem Cells.

In this issue of Cell Stem Cell, Jia et al. (2020) identify residual cancer stem cells (CSCs) as a mechanism of immunotherapy resistance in head and neck squamous cell carcinoma (HNSCC). Remarkably, targeting this population of CSCs can be exploited to potentiate immunotherapy and reduce tumor recurrence and metastasis

Activation of G-Protein Coupled Receptor-Gαi Signaling Increases Keratinocyte Proliferation and Reduces Differentiation, Leading to Epidermal Hyperplasia.

G-protein coupled receptors (GPCRs) and their associated heterotrimeric G proteins impinge on pathways that control epithelial cell self-renewal and differentiation. Although it is known that Gαs protein signaling regulates skin homeostasis in vivo, the role of GPCR-coupled Gαi proteins in the skin is unclear. Here, by using a chemogenetic approach, we demonstrate that GPCR-Gαi activation can regulate keratinocyte proliferation and differentiation and that overactivation of Gαi-signaling in the basal compartment of the mouse skin can lead to epidermal hyperplasia. Our results expand our understanding of the role of GPCR-cAMP signaling in skin homeostasis and reveal overlapping and divergent roles of the cAMP-regulating heterotrimeric Gαs and Gαi proteins in keratinocytes