The mesenchymal status of metastatic cancer cells promotes a stromal crosstalk leading to epithelial re-acquisition and metastatic colonisation

Solid epithelial tumours are complex structures in which the associated stroma supports cancer cells (Quail and Joyce, 2013). During metastatic progression, cancer cells disseminate from their tissue of origin and recapitulate the tumour structure at distant organs, including the stromal compartment. Metastasis initiating cells (MICs) are functionally discriminated among the bulk of cancer cells for their high ability to establish metastasis (Malanchi et al., 2012, Baccelli et al., 2013). Additionally, efficient metastasis requires the expression of specific molecules within the local microenvironment (Oskarsson et al., 2014). Thus, a favourable microenvironment or niche is a crucial early step in metastatic progression. However what features of MICs mediate metastatic niche activation is poorly characterised. One strategy adopted by metastatic cells to disseminate from primary tumours is the activation of the developmental programme epithelial-to-mesenchymal transition (EMT). However, EMT is a reversible programme that needs to be inhibited at the target site for tumour cells to re-acquire epithelial characteristics compatible with metastatic outgrowth (Nieto, 2013). To successfully metastasise cancer cells need to retain self-renewal and growth properties through epithelial plasticity. This implies that during metastasis ‘stemness’ should not be strictly coupled to EMT as previously suggested (Mani et al., 2008). To date, both the potential advantage of disseminated cancer cells mesenchymal status and the source of their epithelial plasticity at the metastatic site remain unknown. In this thesis we use metastatic breast cancer models to elucidate the enhanced niche-induction ability of mesenchymal MICs, its relationship to EMT and the source of its epithelial modulation during metastatic colonisation. Importantly, we identify THBS2 as a novel effector linked to the EMT status of cancer cells that enhances stromal niche activation. Subsequently, the newly activated stroma triggers cancer cell BMP-dependent re-epithelialisation promoting metastatic outgrowth. Thereby, we describe a temporally controlled metastatic colonisation where the EMT status of cancer cells promotes its own inhibition via a cancer cell-stromal crosstalk that initially enhances metastatic niche formation, and ultimately favours a cancer cell proliferative state compatible with metastatic outgrowth

Situación de los jóvenes en el mercado laboral en Castilla y León

El trabajo aborda la situación de los jóvenes en el mercado laboral. En primer lugar se hace mención a la población de Castilla y León comparada con España para luego hacer referencia a características de esta según la formación, el género, o la nacionalidad, entre otras.A continuación se hace un repaso a las reformas laborales en España para ver su influencia en los jóvenes y los beneficios o perjuicios que traían para ellos y el resto de la población.Por último se consideran la población activa, inactiva, tasas de ocupación de paro y más conceptos, sobre la población de Castilla y León en comparación con España pero también en las provincias de Castilla y León las diferencias entre ellas.<br /

Virus-induced gene silencing database for phenomics and functional genomics in Nicotiana benthamiana

Virus-induced gene silencing (VIGS) is an important forward and reverse genetics method for the study of gene function in many plant species, especially Nicotiana benthamiana. However, despite the widespread use of VIGS, a searchable database compiling the phenotypes observed with this method is lacking. Such a database would allow researchers to know the phenotype associated with the silencing of a large number of individual genes without experimentation. We have developed a VIGS phenomics and functional genomics database (VPGD) that has DNA sequence information derived from over 4,000 N. benthamiana VIGS clones along with the associated silencing phenotype for approximately 1,300 genes. The VPGD has a built-in BLAST search feature that provides silencing phenotype information of specific genes. In addition, a keyword-based search function could be used to find a specific phenotype of interest with the corresponding gene, including its Gene Ontology descriptions. Query gene sequences from other plant species that have not been used for VIGS can also be searched for their homologs and silencing phenotype in N. benthamiana. VPGD is useful for identifying gene function not only in N. benthamiana but also in related Solanaceae plants such as tomato and potato. The database is accessible at http://vigs.noble.org.Noble Research Institute and NSF IOS-102564

Ecotypic differentiation and phenotypic plasticity combine to enhance the invasiveness of the most widespread daisy in Chile, Leontodon saxatilis

Dispersal and reproductive traits of successful plant invaders are expected to undergo strong selection during biological invasions. Numerous Asteraceae are invasive and display dimorphic fruits within a single flower head, resulting in differential dispersal pathways - wind-dispersed fruits vs. nondispersing fruits. We explored ecotypic differentiation and phenotypic plasticity of seed output and fruit dimorphisms in exotic Chilean and native Spanish populations of Leontodon saxatilis subsp. rothii. We collected flower heads from populations in Spain and Chile along a rainfall gradient. Seeds from all populations were planted in reciprocal transplant trials in Spain and Chile to explore their performance in the native and invasive range. We scored plant biomass, reproductive investment and fruit dimorphism. We observed strong plasticity, where plants grown in the invasive range had much greater biomass, flower head size and seed output, with a higher proportion of wind-dispersed fruits, than those grown in the native range. We also observed a significant ecotype effect, where the exotic populations displayed higher proportions of wind-dispersed fruits than native populations. Together, these patterns reflect a combination of phenotypic plasticity and ecotypic differentiation, indicating that Leontodon saxatilis has probably increased propagule pressure and dispersal distances in its invasive range to enhance its invasiveness.Irene Martín-Forés, Marta Avilés, Belén Acosta-Gallo, Martin F. Breed, Alejandro del Pozo, José M. de Miguel, Laura Sánchez-Jardón, Isabel Castro, Carlos Ovalle, Miguel A. Casad

Effects of cell tension on the small GTPase Rac

Cells in the body are subjected to mechanical stresses such as tension, compression, and shear stress. These mechanical stresses play important roles in both physiological and pathological processes; however, mechanisms transducing mechanical stresses into biochemical signals remain elusive. Here, we demonstrated that equibiaxial stretch inhibited lamellipodia formation through deactivation of Rac. Nearly maximal effects on Rac activity were obtained with 10% strain. GAP-resistant, constitutively active V12Rac reversed this inhibition, supporting a critical role for Rac inhibition in the response to stretch. In contrast, activation of endogenous Rac with a constitutively active nucleotide exchange factor did not, suggesting that regulation of GAP activity most likely mediates the inhibition. Uniaxial stretch suppressed lamellipodia along the sides lengthened by stretch and increased it at the adjacent ends. A fluorescence assay for localized Rac showed comparable changes in activity along the sides versus the ends after uniaxial stretch. Blocking polarization of Rac activity by expressing V12Rac prevented subsequent alignment of actin stress fibers. Treatment with Y-27632 or ML-7 that inhibits myosin phosphorylation and contractility increased lamellipodia through Rac activation and decreased cell polarization. We hypothesize that regulation of Rac activity by tension may be important for motility, polarization, and directionality of cell movement

Members of the α-amylase inhibitors family from wheat endosperm are major allergens associated with baker's asthma

AbstractWe have identified the major antigens or IgE binding components from wheat flour. Thirty-five sera from patients with baker's asthma were used to analyze the reaction with wheat salt-soluble proteins. We found a 15 kDa SDS-PAGE band which reacted with all sera tested. Purified members of the α-amylase inhibitor family, which are the main components of the 15 kDa band, were recognized by specific IgE when tested with a pool of reactive sera. Immunodetection after two-dimensional electrophoretic fractionation of crude inhibitor preparations from wheat endosperms also detected several inhibitor subunits as major low-molecular-weight allergens

Canódromo madrileño

La importancia constructiva y estructural de esta obra, cuyo voladizo de tribunas constituye una de las mayores realizaciones resueltas en estructura laminar, son debidamente estudiadas en su triple aspecto de: proyecto, construcción y cálculo

Ecotypic differentiation and phenotypic plasticity combine to enhance the invasiveness of the most widespread daisy in Chile, Leontodon saxatilis

Dispersal and reproductive traits of successful plant invaders are expected to undergo strong selection during biological invasions. Numerous Asteraceae are invasive and display dimorphic fruits within a single flower head, resulting in differential dispersal pathways - wind-dispersed fruits vs. nondispersing fruits. We explored ecotypic differentiation and phenotypic plasticity of seed output and fruit dimorphisms in exotic Chilean and native Spanish populations of Leontodon saxatilis subsp. rothii. We collected flower heads from populations in Spain and Chile along a rainfall gradient. Seeds from all populations were planted in reciprocal transplant trials in Spain and Chile to explore their performance in the native and invasive range. We scored plant biomass, reproductive investment and fruit dimorphism. We observed strong plasticity, where plants grown in the invasive range had much greater biomass, flower head size and seed output, with a higher proportion of wind-dispersed fruits, than those grown in the native range. We also observed a significant ecotype effect, where the exotic populations displayed higher proportions of wind-dispersed fruits than native populations. Together, these patterns reflect a combination of phenotypic plasticity and ecotypic differentiation, indicating that Leontodon saxatilis has probably increased propagule pressure and dispersal distances in its invasive range to enhance its invasiveness

ECM deposition is driven by caveolin-1-dependent regulation of exosomal biogenesis and cargo sorting.

The composition and physical properties of the extracellular matrix (ECM) critically influence tumor progression, but the molecular mechanisms underlying ECM layering are poorly understood. Tumor-stroma interaction critically depends on cell communication mediated by exosomes, small vesicles generated within multivesicular bodies (MVBs). We show that caveolin-1 (Cav1) centrally regulates exosome biogenesis and exosomal protein cargo sorting through the control of cholesterol content at the endosomal compartment/MVBs. Quantitative proteomics profiling revealed that Cav1 is required for exosomal sorting of ECM protein cargo subsets, including Tenascin-C (TnC), and for fibroblast-derived exosomes to efficiently deposit ECM and promote tumor invasion. Cav1-driven exosomal ECM deposition not only promotes local stromal remodeling but also the generation of distant ECM-enriched stromal niches in vivo. Cav1 acts as a cholesterol rheostat in MVBs, determining sorting of ECM components into specific exosome pools and thus ECM deposition. This supports a model by which Cav1 is a central regulatory hub for tumor-stroma interactions through a novel exosome-dependent ECM deposition mechanism.This study was supported by the Ministerio de Ciencia, Innovación y Universidades (CSD2009-0016, SAF2014-51876-R, SAF2017-83130-R, BFU2016-81912-REDC, and IGP-SO-MINSEV1512-07-2016); the Fundació La Marató de TV3 (385/C/2019); the Worldwide Cancer Research Foundation (AICR 15-0404); and Fondo Europeo de Desarrollo Regional “Una manera de hacer Europa” (to M.Á. del Pozo). M.Á. del Pozo’s group received funding from the European Union Horizon 2020 research and innovation program under Marie Sklodowska-Curie grant agreement no. 641639. M.Á. del Pozo is a member of the Tec4Bio consortium (ref. S2018/NMT4443; Actividades de I+D entre Grupos de Investigación en Tecnologías, Comunidad Autónoma de Madrid/FEDER, Spain). J. Balsinde was supported by Ministerio de Ciencia, Innovación y Universidades grants SAF2013-48201-R and SAF2016-80883-R, and G. Orend was supported by Institut National de la Santé et de la Recherche Médicale, the University of Strasbourg, the Ligue Contre le Cancer, and the Institut National du Cancer (ref. TENPLAMET). L. Albacete-Albacete was supported by a Ministerio de Ciencia, Innovación y Universidades predoctoral fellowship associated with the Severo Ochoa Excellence program (ref. SVP-2013-06789). I. Navarro-Lérida was supported by a postdoctoral fellowship from the Asociación Española Contra el Cáncer (ref. INVES191NAVA). The Centro Nacional de Investigaciones Cardiovasculares Carlos III is supported by the Ministerio de Ciencia e Innovación and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505).S