The stress connection in cancer: the adrenergic fuelling of breast tumors

Cancer progression involves complex interactions between tumor cells and the surrounding microenvironment. Chronic psychosocial stress and sympathetic nervous system activation lead to abnormal catecholamine release, impacting tumor cells directly and indirectly and fuelling cancer-promoting effects. However, the same adrenergic Receptor (AR) that mediate these effects could also convey exercise-related beneficial changes. Epidemiological studies show conflicting associations between stress, AR inhibitors, and breast cancer (BC) metastatic progression. Adrenergic sympathetic stress triggers sustained inflammatory and hypoxic-related signaling pathways, alters function and distribution of immune cell populations, and remodels blood vessels, leading to immunosuppression and premetastatic site formation. Activated AR initiate feedback loops with tyrosine kinase receptors and chemokine receptors, affecting stem-related transcription factors, pro-inflammatory mediators, angiogenic factors, and energy metabolism regulators, promoting tumor growth and invasion. Understanding molecular mechanisms of agonistic and antagonistic AR ligands and crosstalk with other signaling pathways is crucial for developing effective therapies targeting adrenergic-driven BC progressionP2022/BMD-7209/INTEGRAMUNE-CM, SEV2016-064

GRK2-Dependent HuR Phosphorylation Regulates HIF1α Activation under Hypoxia or Adrenergic Stress.

Adaptation to hypoxia is a common feature in solid tumors orchestrated by oxygen-dependent and independent upregulation of the hypoxia-inducible factor-1α (HIF-1α). We unveiled that G protein-coupled receptor kinase (GRK2), known to be overexpressed in certain tumors, fosters this hypoxic pathway via phosphorylation of the mRNA-binding protein HuR, a central HIF-1α modulator. GRK2-mediated HuR phosphorylation increases the total levels and cytoplasmic shuttling of HuR in response to hypoxia, and GRK2-phosphodefective HuR mutants show defective cytosolic accumulation and lower binding to HIF-1α mRNA in hypoxic Hela cells. Interestingly, enhanced GRK2 and HuR expression correlate in luminal breast cancer patients. GRK2 also promotes the HuR/HIF-1α axis and VEGF-C accumulation in normoxic MCF7 breast luminal cancer cells and is required for the induction of HuR/HIF1-α in response to adrenergic stress. Our results point to a relevant role of the GRK2/HuR/HIF-1α module in the adaptation of malignant cells to tumor microenvironment-related stresses.This research was funded by the Instituto de Salud Carlos III: PI17-00576; Ministerio de Economia, Industria y Competitividad, Gobierno de Espana: SAF2017-84125-R; Ministerio de Economia, Industria y Competitividad, Gobierno de Espana: SAF2017-87301-R; Instituto de Salud Carlos III: CIBERCV CB16/11/00278; Instituto de Salud Carlos III: PI14-00435; Fundacion Ramon Areces and the Comunidad de Madrid: B2017/BMD-3671-INFLAMUNE.S

Cell-Type Specific GRK2 Interactomes: Pathophysiological Implications

G protein-coupled receptor kinase 2 (GRK2) is emerging as a key hub in cell signaling cascades. In addition to modulating activated G protein-coupled receptors, GRK2 can phosphorylate and/or functionally interact with a complex network of cellular proteins in a cell-type and physiological context-dependent way. A combination of such canonical and noncanonical interactions underlies the participation of this kinase in the control of cell migration, proliferation or metabolism and in integrated processes at the tissue or whole organism levels, such as angiogenesis, cardiovascular function, or insulin resistance, among others. Its role as a signaling node and the fact that altered levels of GRK2 are detected in a variety of pathological conditions put forward this protein as a potentially relevant diagnostic and therapeutic targe

Developmental and tumoral vascularization is regulated by G protein-coupled receptor kinase 2

Tumor vessel dysfunction is a pivotal event in cancer progression. Using an in vivo neovascularization model, we identified G protein–coupled receptor kinase 2 (GRK2) as a key angiogenesis regulator. An impaired angiogenic response involving immature vessels was observed in mice hemizygous for Grk2 or in animals with endothelium-specific Grk2 silencing. ECs isolated from these animals displayed intrinsic alterations in migration, TGF-β signaling, and formation of tubular networks. Remarkably, an altered pattern of vessel growth and maturation was detected in postnatal retinas from endothelium-specific Grk2 knockout animals. Mouse embryos with systemic or endothelium-selective Grk2 ablation had marked vascular malformations involving impaired recruitment of mural cells. Moreover, decreased endothelial Grk2 dosage accelerated tumor growth in mice, along with reduced pericyte vessel coverage and enhanced macrophage infiltration, and this transformed environment promoted decreased GRK2 in ECs and human breast cancer vessels. Our study suggests that GRK2 downregulation is a relevant event in the tumoral angiogenic switch.Our laboratory is funded by grants from Ministerio de Educación y Ciencia (SAF2011-23800), Fundación Ramón Areces, The Cardiovascular Network (RECAVA) of Ministerio Sanidad y Consumo-Instituto Carlos III (RD06-0014/0037 and RD12/0042/0012), and Comunidad de Madrid (S-2010/BMD- 2332) to F. Mayor Jr. and Instituto Carlos III (PI11/00859), Fundación Ramón Areces, and Fundación Rodríguez Pascual to P. Penela. Marta Mendiola is supported by a postdoctoral research contract from Fondo de Investigación Sanitaria (“Sara Borrell” Programme), Instituto de Salud Carlos III

The TINCR ubiquitin-like microprotein is a tumor suppressor in squamous cell carcinoma

The TINCR (Terminal differentiation-Induced Non-Coding RNA) gene is selectively expressed in epithelium tissues and is involved in the control of human epidermal differentiation and wound healing. Despite its initial report as a long non-coding RNA, the TINCR locus codes for a highly conserved ubiquitin-like microprotein associated with keratinocyte differentiation. Here we report the identification of TINCR as a tumor suppressor in squamous cell carcinoma (SCC). TINCR is upregulated by UV-induced DNA damage in a TP53-dependent manner in human keratinocytes. Decreased TINCR protein expression is prevalently found in skin and head and neck squamous cell tumors and TINCR expression suppresses the growth of SCC cells in vitro and in vivo. Consistently, Tincr knockout mice show accelerated tumor development following UVB skin carcinogenesis and increased penetrance of invasive SCCs. Finally, genetic analyses identify loss-of-function mutations and deletions encompassing the TINCR gene in SCC clinical samples supporting a tumor suppressor role in human cancer. Altogether, these results demonstrate a role for TINCR as protein coding tumor suppressor gene recurrently lost in squamous cell carcinomas.This work was supported by NIH grants P30 CA013696 (Confocal and Specialized Microscopy Shared Resource, Proteomics Shared Resource, Molecular Pathology Shared Resource, Genomics Shared Resource, Herbert Irving Comprehensive Cancer Center), R01 GM102491 (A.S.), K01 CA249038 (T.F.M.), P30 AR069632 (epiCURE SCIM and SIND Core Facilities) and R35 CA210065 (A.A.F.); Dr. Frederick Paulsen Chair/Ferring Pharmaceuticals (A.S.); Plan Nacional de I + D + I/ISCIII grants PI16/00280 and PI19/00560 (J.M.G.-P.), and PI18/01527 (M.F.F. and A.F.F.); CIBERONC grant CB16/12/00390 (J.P.R.), and the FEDER Funding Program from the European Union. Crystallization screening at the National Crystallization Center at HWI was supported through NIH grant R24GM141256. This work used the NE-CAT 24-ID-E beamline (GM124165) and an Eiger detector (OD021527) at the APS (DE-AC02-06CH11357). LMP was supported by a Leukemia and Lymphoma Society Career Development fellowship (grant #5461-18). J.A.B. was the Candy and William Raveis Fellow of the Damon Runyon-Sohn Foundation Pediatric Cancer Fellowship Award (grant no. DRSG-31-19) and supported by the National Cancer Institute of the National Institutes of Health (award no. K99CA267168). R.G.-D. is a recipient of a Severo Ochoa predoctoral fellowship from the Principado de Asturias (grant # BP19-063).Peer reviewe

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Precision nutrition and cancer relapse prevention: A systematic literature review

This article belongs to the Special Issue Dietary Patterns, Dietary Indices for Colorectal Cancer, Mortality and the Related Disease.Cancer mortality rates are undergoing a global downward trend; however, metastasis and relapse after surgery and adjuvant treatments still correlate with poor prognosis and represent the most significant challenges in the treatment of this disease. Advances in genomics, metabolomics, and proteomics are improving our understanding regarding cancer metabolic diversity, resulting in detailed classifications of tumors and raising the effectiveness of precision medicine. Likewise, the growing knowledge of interactions between nutrients and the expression of certain genes could lead to cancer therapies based on precision nutrition strategies. This review aims to identify the recent advances in the knowledge of the mechanistic role of bioactive phytochemicals in foodstuffs in tumor progression, metastasis, and chemo-resistance in order to assess their potential use in precision nutrition therapies targeting relapse in lung, breast, colon, and prostate cancer, and leukemia. A considerable number of bioactive phytochemicals in foodstuffs were identified in the literature with proven effects modulating tumor growth, progression, and metastasis. In addition, the use of foodstuffs in cancer, and specifically in relapse therapies, is being reinforced by the development of different formulations that significantly increase the therapeutic efficiency of these products. This can open the possibility for testing combinations of bioactive phytochemicals with cancer relapse treatments as a potential prevention strategy.This research is part of the work plan of Project AGL2016-76736-C3 supported by the Spanish Ministerio de Ciencia, Innovación y Universidades; Project P2018/BAA-4343-ALIBIRD2020-CM supported by the Regional Government of Comunidad de Madrid (V PRICYT).Peer reviewe

Regulation of GRK2 by Mdm2 and the APC/C complex: a way to fine-tune dynamics and faithful progression of the cell cycle

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 15-09-2017Esta tesis tiene embargado el acceso al texto completo hasta el 15-03-2019La degradación proteasomal de quinasas esenciales es el mecanismo de regulación mayoritario en el control del ciclo celular. Aunque inicialmente caracterizada como uno de los principales efectores de la desensibilización de los receptores acoplados a proteínas G (GPCRs), la quinasa GRK2 se perfila como un nodo emergente en la señalización celular por su capacidad para regular distintas proteínas señalizadoras y procesos celulares. Se ha demostrado que el aumento de los niveles de esta quinasa favorece la señalización en vías de factores de crecimiento y la proliferación y la supervivencia de distintos tipos de células tumorales de mama. Por otra parte, hemos descrito que fluctuaciones en GRK2 parecen tener un papel regulador de GRK2 en la progresión del ciclo celular, mientras que su estabilización disminuye la eficacia con la que la célula detiene el ciclo en respuesta a sustancias genotóxicas. Por tanto, estudiar cómo y por qué cambian los niveles de GRK2 en las distintas fases del ciclo celular podría ayudar a entender el papel de esta quinasa en el crecimiento tumoral. Hemos descubierto que los niveles de GRK2 disminuyen progresivamente durante la fase G2 y mitosis como consecuencia de una cooperación secuencial de las E3 ligasas Mdm2 y APC/C. Durante la fase G2, el complejo CDK2/Ciclina A fosforila a GRK2, facilitando la interacción con la prolil-isomerasa Pin1 y permitiendo su posterior ubiquitinación por Mdm2. Por el contrario, el complejo APC/CCdc20 es el responsable de promover la degradación de GRK2 en mitosis, reconociendo un motivo de destrcucción D-Box en su secuencia en un proceso insensible al punto de restricción del huso. Por otra parte, en la fase G1 varios mecanismos dependientes de la quinasa CK2 protegen a GRK2 de la acción del complejo APC/CCdh1, permitiendo la recuperación de sus niveles. Si se impide que tengan lugar estos procesos secuenciales de disminución y recuperación de GRK2, se producen alteraciones significativas en la proliferación, duración de la fase G1 y progresión de la mitosis. Nuestros datos sugieren que estas alteraciones pueden estar relacionadas con la demostrada influencia de GRK2 en la separación de centrosomas impulsada por EGF en G2 y con el papel de GRK2 en la modulación de la dinámica de microtúbulos mediante la fosforilación de la tubulin-deacetilasa HDAC6. Resulta interesante que la ganancia de función de GRK2 en G1 parece contribuir a la adaptación de dinámicas de ciclo celular a decisiones de destino celular, ya que el acortamiento de la fase G1 del mutante DBox de GRK2 corresponde con ciertas características de células indiferenciadas. Además, nuestros datos apuntan a posibles interacciones de GRK2 con importantes reguladores del proceso de citoquinesis. Curiosamente, hemos detectado la presencia de GRK2 en el midbody y hemos visto que la expresión de mutantes defectivos en estabilidad o actividad afecta al progreso de la citoquinesis y provoca cambios en el contenido proteico del midbody; probablemente alterando puntos críticos del proceso como la organización del anillo contráctil, el posicionamiento y hundimiento del surco de división y a la abscisión final del midbody. En resumen, nuestros resultados sugieren que una degradación inadecuada de GRK2 durante el ciclo celular puede comprometer la fidelidad de la división celular por medio de una rápida progresión en G1 y el deterioro del ensamblaje y la funcionalidad del huso mitótico en la mitosis, así como en la citoquinesis, contribuyendo en conjunto al aumento de poliploidía e inestabilidad genómica.La realización de esta Tesis ha sido posible gracias a fondos de Proyectos I+D+i correspondientes al Programa Estatal de Investigación, Desarrollo e Innovación Orientada a los Retos de la Sociedad del Ministerio de Economía y Competitividad, y de la Fundación Severo Ochoa. La autora también ha recibido apoyo a través de becas de EMBO, IUBMB, FEBS y SEBBM para asistencia a congresos

La Emigración Española en Toulouse: Perspectiva Histórica y Situación Actual

La emigración de españoles a la ciudad de Toulouse, Francia, ha sido una constante desde finales del Siglo XIX hasta nuestros días. Este fenómeno ha evolucionado a lo largo de diferentes etapas. Cada una de ellas ha presentado unas características y condicionantes propias que marcan el perfil del “emigrado”. Aplicando una metodología cualitativa, se contrasta el marco teórico, a través de testimonios reales de los propios emigrados, que narraran su experiencia, opiniones y perspectivas. Para concluir, se constatan similitudes y diferencias entre diferentes etapas históricas

Bodas de 1392 en 2013: Una aproximación a las prácticas del Matrimonio en Afganistán

Cuando en Afganistán acaba de celebrar el comienzo del año 1392 según su calendario, algunos de los usos, costumbres y estructura social de este país nos parecen propios de otra era en la Europa del Siglo XXI De este país sólo nos llegan noticias negativas de conflictos tribales, mujeres cubiertas con burkas, matrimonios forzosos, bodas de niñas con hombre muy mayores, violencia…pero ¿es esa toda la realidad? ¿Qué motivos provocan que perduren estas prácticas tan arcaicas? ¿Qué consecuencias tienen? ¿Y qué dice la legislación del país?¿cómo viven sus protagonistas estas cuestiones? Este estudio trata de asomarnos a las costumbres relativas al matrimonio en la provincia de Badghis, (Afganistán), descubrir el valor que tiene para los habitantes de estas zonas, las variantes que adopta y los cambios que ha experimentado en los últimos tiempos