Prolyl-isomerase Pin1 controls normal and cancer stem cells of the breast by counteracting the Fbxw7-oncosuppressive barrier on the Notch signalling pathway

2012/2013Cancer stem cells (CSCs) are proposed to be responsible for breast cancer heterogeneity, chemotherapeutic treatment failure, metastatic spread and disease recurrence. The precise identification of the molecular bases that govern the induction and maintenance of CSCs and their aggressive phenotypes is of utmost importance, since it may provide the rational to develop effective therapeutic strategies. In particular there is a considerable effort in finding common pathways, mutations or histological features that might be targeted for therapy, overcoming breast cancer heterogeneity. Here we now demonstrate that CSC self-renewal, chemoresistance, tumour growth and metastases formation capabilities’ are under direct control of Pin1’s enzymatic activity on the Notch signalling pathway. In particular Pin1 protects the nuclear activated forms of Notch1 and Notch4 (N1/4-ICD) from their E3-ubiquitin-ligase Fbxw7α, thereby boosting their protein levels and transcriptional activity. Fbxw7α acts as a potent inhibitor of CSCs maintenance by promoting protein degradation of N1- and N4-ICD, and, as a consequence, this ubiquitin-ligase strongly decreased tumour growth and metastases dissemination in vivo. Interestingly, concomitant over-expression of Pin1 almost completely recovered all these aggressive breast cancer traits. In tissues from breast cancer patients, we observed Notch signalling over-activation despite presence of the negative regulator Fbxw7α, which relied on high Pin1 protein levels. Notably, activation of the Notch-Pin1 axis correlated with poor prognosis in these patients. As a consequence of our findings, suppression of Pin1 holds promise in reverting aggressive phenotypes in breast cancer though shrinkage of CSCs number and a concomitant gain in chemosensitivity, carrying important implications for breast cancers therapy.XXVI Ciclo198

Oncogenic Hijacking of the PIN1 Signaling Network

Cellular choices are determined by developmental and environmental stimuli through integrated signal transduction pathways. These critically depend on attainment of proper activation levels that in turn rely on post-translational modifications (PTMs) of single pathway members. Among these PTMs, post-phosphorylation prolyl-isomerization mediated by PIN1 represents a unique mechanism of spatial, temporal and quantitative control of signal transduction. Indeed PIN1 was shown to be crucial for determining activation levels of several pathways and biological outcomes downstream to a plethora of stimuli. Of note, studies performed in different model organisms and humans have shown that hormonal, nutrient, and oncogenic stimuli simultaneously affect both PIN1 activity and the pathways that depend on PIN1-mediated prolyl-isomerization, suggesting the existence of evolutionarily conserved molecular circuitries centered on this isomerase. This review focuses on molecular mechanisms and cellular processes like proliferation, metabolism, and stem cell fate, that are regulated by PIN1 in physiological conditions, discussing how these are subverted in and hijacked by cancer cells. Current status and open questions regarding the use of PIN1 as biomarker and target for cancer therapy as well as clinical development of PIN1 inhibitors are also addressed

Glucocorticoid receptor signalling activates YAP in breast cancer

The Hippo pathway is an oncosuppressor signalling cascade that plays a major role in the control of cell growth, tissue homoeostasis and organ size. Dysregulation of the Hippo pathway leads to aberrant activation of the transcription co-activator YAP (Yes-associated protein) that contributes to tumorigenesis in several tissues. Here we identify glucocorticoids (GCs) as hormonal activators of YAP. Stimulation of glucocorticoid receptor (GR) leads to increase of YAP protein levels, nuclear accumulation and transcriptional activity in vitro and in vivo. Mechanistically, we find that GCs increase expression and deposition of fibronectin leading to the focal adhesion-Src pathway stimulation, cytoskeleton-dependent YAP activation and expansion of chemoresistant cancer stem cells. GR activation correlates with YAP activity in human breast cancer and predicts bad prognosis in the basal-like subtype. Our results unveil a novel mechanism of YAP activation in cancer and open the possibility to target GR to prevent cancer stem cells self-renewal and chemoresistance

MDP, a database linking drug response data to genomic information, identifies dasatinib and statins as a combinatorial strategy to inhibit YAP/TAZ in cancer cells

Targeted anticancer therapies represent the most effective pharmacological strategies in terms of clinical responses. In this context, genetic alteration of several oncogenes represents an optimal predictor of response to targeted therapy. Integration of large-scale molecular and pharmacological data from cancer cell lines promises to be effective in the discovery of new genetic markers of drug sensitivity and of clinically relevant anticancer compounds. To define novel pharmacogenomic dependencies in cancer, we created the Mutations and Drugs Portal (MDP, http://mdp.unimore.it), a web accessible database that combines the cell-based NCI60 screening of more than 50,000 compounds with genomic data extracted from the Cancer Cell Line Encyclopedia and the NCI60 DTP projects. MDP can be queried for drugs active in cancer cell lines carrying mutations in specific cancer genes or for genetic markers associated to sensitivity or resistance to a given compound. As proof of performance, we interrogated MDP to identify both known and novel pharmacogenomics associations and unveiled an unpredicted combination of two FDA-approved compounds, namely statins and Dasatinib, as an effective strategy to potently inhibit YAP/TAZ in cancer cells

Investigating elevational gradients of species richness in a Mediterranean plant hotspot using a published flora

The Apuan Alps are one of the most peculiar mountain chain in the Mediterranean, being very close to the coastline and reaching an elevation of almost 2000 m. Based on published flora, we investigated the distribution of plant species richness along the whole elevational gradient of this chain considering: (i) all species, (ii) endemic versus alien species; and (iii) functional groups of species based on Raunkiær life forms (RLF). Generalized Linear Models (GLMs) were used to analyse richness patterns along the elevational gradient, and elevational richness models versus the area of the elevational belts were fitted to test the effect of surface area. Our results showed decreasing species richness with increasing elevation. In contrast, endemic species richness increased along the elevational gradient. Alien species were mainly distributed at low elevations, but this result should be taken with caution since we used historical data. Species life forms were not equally distributed along the elevation gradient: chamaephytes and hemicryptophytes were the richest groups at high elevations, while therophytes showed highest species richness at low elevations. Our findings suggest that in the Apuan Alps there is a major elevational gradient in species composition that could reflect plant evolutionary history. Furthermore, we highlight the key role of published floras as a relevant source of biodiversity data.publishedVersio

Investigating sacred natural sites and protected areas for forest area changes in Italy

Forests will be critical to mitigate the effects of climate and global changes. Therefore, knowledge on the drivers of forest area changes are important. Although the drivers of deforestation are well known, drivers of afforestation are almost unexplored. Moreover, protected areas (PAs) effectively decrease deforestation, but other types of area-based conservation measures exist. Among these, sacred natural sites (SNS) deliver positive conservation out- comes while making up an extensive “shadow network” of conservation. How- ever, little is known on the capacity of SNS to regulate land-use changes. Here, we explored the role of SNS and PAs as drivers of forest loss and forest gain in Italy between 1936 and 2018. We performed a descriptive analysis and modeled forest gain and forest loss by means of spatial binomial generalized linear models with residual autocovariates. The main drivers of forest area changes were geographical position and elevation, nonetheless SNS and PAs significantly decreased forest loss and increased forest gain. Although the neg- ative relationship between SNS and forest loss is a desirable outcome, the posi- tive relationship with forest gain is concerning because it could point to abandonment of cultural landscapes with consequent loss of open habitats. We suggest a legal recognition of SNS and an active ecological monitoring and planning to help maintain their positive role in biodiversity conservation. As a novel conservation planning approach, SNS can be used as stepping stones between PAs increasing connectivity and also to conserve small habitat patches threatened by human activities

AMS-VegBank: a new database of vegetation plots for the Italian territory

The importance of collection, storage and exchange of georeferenced vegetation plot-based data has significantly grown in the recent decades, because of the new potentialities offered by ecoinformatics. In this article we introduce the Alma Mater Studiorum – University of Bologna vegetation database (AMS-VegBank; GIVD code EU-IT-021) compiling 17,505 georeferenced vegetation-plot observations within a time span of 90 years. This database includes 337,799 occurrence data of vascular plant species, belonging to many different habitat types. The historical relevance of the presented database is highlighted by the presence of some of the most ancient vegetation-plot observations in Europe (years 1930–1938). The geographic coverage of the database is mostly for Italian territory but it includes also data from other countries. The thematic focuses represented in the database are various, such as small Mediterranean islands, the Dolomite Mountains and the Italian National Parks. The large amount of historical plots available for the country not previously included in existing databases, combined with the constant action to improve the georeferencing of existing data and the addition of new data, highlight the uniqueness of this database. AMS-VegBank represents thus an important tool for studying plant biodiversity within the context of continental and global vegetation plot databases

Probabilistic and preferential sampling approaches offer integrated perspectives of Italian forest diversity

Aim: Assessing the performances of different sampling approaches for documenting community diversity may help to identify optimal sampling efforts and strategies, and to enhance conservation and monitoring planning. Here, we used two data sets based on probabilistic and preferential sampling schemes of Italian forest vegetation to analyze the multifaceted performances of the two approaches across three major forest types at a large scale. Location: Italy. Methods: We pooled 804 probabilistic and 16,259 preferential forest plots as samples of vascular plant diversity across the country. We balanced the two data sets in terms of sizes, plot size, geographical position, and vegetation types. For each of the two data sets, 1000 subsets of 201 random plots were compared by calculating the shared and exclusive indicator species, their overlap in the multivariate space, and the areas encompassed by spatially-constrained rarefaction curves. We then calculated an index of performance using the ratio between the additional and total information collected by each sampling approach. The performances were tested and evaluated across the three major forest types. Results: The probabilistic approach performed better in estimating species richness and diversity of species assemblages, but did not detect other components of the regional diversity, such as azonal forests. The preferential approach outperformed the probabilistic approach in detecting forest-specialist species and plant diversity hotspots. Conclusions: Using a novel workflow based on vegetation-plot exclusivities and commonalities, our study suggests probabilistic and preferential sampling approaches are to be used in combination for better conservation and monitor planning purposes to detect multiple aspects of plant community diversity. Our findings can assist the implementation of national conservation planning and large-scale monitoring of biodiversit

A grid-based map for the biogeographical regions of Europe

© Pensoft Publishers. Background Biogeographical units are widely adopted in ecological research and nature conservation management, even though biogeographical regionalisation is still under scientific debate. The European Environment Agency provided an official map of the European Biogeographical Regions (EBRs), which contains the official boundaries used in the Habitats and Birds Directives. However, these boundaries bisect cells in the official EU 10 km x 10 km grid used for many purposes, including reporting species and habitat data, meaning that 6881 cells overlap two or more regions. Therefore, superimposing the EBRs vector map over the grid creates ambiguities in associating some cells with European Biogeographical Regions. New information To provide an operational tool to unambiguously define the boundaries of the eleven European Biogeographical Regions, we provide a specifically developed raster map of Grid-Based European Biogeographical Regions (GB-EBRs). In this new map, the borders of the EBRs are reshaped to coherently match the standard European 10 km x 10 km grid imposed for reporting tasks by Article 17 of the Habitats Directive and used for many other datasets. We assign each cell to the EBR with the largest area within the cell