Hyaluronan-Derived Swelling of Solid Tumors, the Contribution of Collagen and Cancer Cells, and Implications for Cancer Therapy

AbstractDespite the important role that mechanical forces play in tumor growth and therapy, the contribution of swelling to tumor mechanopathology remains unexplored. Tumors rich in hyaluronan exhibit a highly negative fixed charge density. Repulsive forces among these negative charges as well as swelling of cancer cells due to regulation of intracellular tonicity can cause tumor swelling and development of stress that might compress blood vessels, compromising tumor perfusion and drug delivery. Here, we designed an experimental strategy, using four orthotopic tumor models, to measure swelling stress and related swelling to extracellular matrix components, hyaluronan and collagen, as well as to tumor perfusion. Subsequently, interventions were performed to measure tumor swelling using matrix-modifying enzymes (hyaluronidase and collagenase) and by repurposing pirfenidone, an approved antifibrotic drug. Finally, in vitro experiments on cancer cell spheroids were performed to identify their contribution to tissue swelling. Swelling stress was measured in the range of 16 to 75 mm Hg, high enough to cause vessel collapse. Interestingly, while depletion of hyaluronan decreased swelling, collagen depletion had the opposite effect, whereas the contribution of cancer cells was negligible. Furthermore, histological analysis revealed the same linear correlation between tumor swelling and the ratio of hyaluronan to collagen content when data from all tumor models were combined. Our data further revealed an inverse relation between tumor perfusion and swelling, suggesting that reduction of swelling decompresses tumor vessels. These results provide guidelines for emerging therapeutic strategies that target the tumor microenvironment to alleviate intratumoral stresses and improve vessel functionality and drug delivery

D1.15 Impact Assessment Report for RP 2

This deliverable provides the impact assessment report for RP2 (M16-M30). It provides an update on the overall and specific objectives of the EXCELSIOR project that have been achieved within RP2. This task undertakes the establishment of a methodology for the yearly monitoring of the impact of the different activities carried out by Eratosthenes Centre of Excellence (ECoE) and its partners through EXCELSIOR against a set of quantified targets. The list of Key Performance Indicators established in D1.12 has been revised based on the comments received by the EXCELSIOR project reviewers on 23 June 2021 following the first project review. This list is hereby updated to reflect the activities of RP2. By monitoring the impact for the RP2, it will provide direction of the activities needed to fulfil the KPIs for the following reporting periods. The impact assessment report will be used to assess the implementation of the work plan and adjust the activities in agreement with WP and task Leaders to ensure the achievement of the Project’s strategic objectives. WP1 provides the KPI monitoring framework and general quality processes, while the WP3 defines concrete actions affecting all other WPs for meeting the Impact KPIs. This task’s activities will be coordinated with WP3 activities on strategy definition as a continuous process, in order to update the human resources, infrastructure acquisition and overall work plan and to meet new priorities identified. The analysis outputs will update the Project Action Plan of Task 1.1. The following activities were examined and assessed according to the KPIs. These activities include proposals, dissemination events, publications, academia, networks, etc. The impact for each activity was also included

ERATOSTHENES: Excellence Research Centre for Earth Surveillance and Space-Based Monitoring of the Environment through the EXCELSIOR Horizon 2020 Teaming Project

Geophysical Research Abstracts, 2018, Volume 20, EGU2018-7390The aim of this paper is to present our vision to upgrade the existing ERATOSTHENES Research Centre (ERC) established within the Cyprus University of Technology (CUT) into a sustainable, viable and autonomous Centre of Excellence (CoE) for Earth Surveillance and Space-Based Monitoring of the Environment, which will provide the highest quality of related services on the National, European and International levels. EXCELSIOR is a Horizon 2020 Teaming project which addresses a specific challenge defined by the work program, namely, the reduction of substantial disparities in the European Union by supporting research and innovation activities and systems in low performing countries. It also aims at establishing long-term and strategic partnerships between the Teaming partners, thus reducing internal research and innovation disparities within European Research and Innovation landscape. The proposed CoE envisions the upgrading of the existing ERC into an inspiring environment for conducting basic and applied research and innovation in the areas of the integrated use of remote sensing and space-based techniques for monitoring the environment. Environment has been recognized by the Smart Specialization Strategy of Cyprus as the first horizontal priority for future growth of the island. The foreseen upgrade will regard the expansion of this vision to systematic monitoring of the environment using Earth Observation, space and ground based integrated technologies. Such an approach will lead to the systematic monitoring of the the Environment. Five partners have united to upgrade the existing ERC into a CoE, with the common vision to become a world-class innovation, research and education centre, actively contributing to the European Research Area (ERA). More specifically, the Teaming project is a team effort between the Cyprus University of Technology (CUT, acting as the coordinator), the German Aerospace Centre (DLR), the National Observatory of Athens (NOA), the German Leibniz Institute for Tropospheric Research (TROPOS) and the Cyprus Department of Electronic Communications of the Ministry of Transport, Communications and Works (DEC-MTCW)

The ERATOSTHENES Centre of Excellence (ECoE) as a digital innovation hub for Earth observation

The "EXCELSIOR" H2020 Widespread Teaming Phase 2 Project: ERATOSTHENES: EXcellence Research Centre for Earth SurveiLlance and Space-Based MonItoring Of the EnviRonment is supported from the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 857510 for a 7 year project period to establish a Centre of Excellence in Cyprus. As well, the Government of the Republic of Cyprus is providing additional resources to support the establishment of the ERATOSTHENES Centre of Excellence (ECoE) in Cyprus. The ECoE seeks to fill the gap by assisting in the spaceborne Earth Observation activities in the Eastern Mediterranean and become a regional key player in the Earth Observation (EO) sector. There are distinct needs and opportunities that motivate the establishment of an Earth Observation Centre of Excellence in Cyprus, which are primarily related to the geostrategic location of the European Union member state of Cyprus to examine complex scientific problems and address user needs in the Eastern Mediterranean, Middle East and Northern Africa (EMMENA), as well as South-East Europe. An important objective of the ECoE is to be a Digital Innovation Hub and a Research Excellence Centre for EO in the EMMENA region, which will establish an ecosystem where state-of-the-art sensing technology, cutting-edge research, targeted education services, and entrepreneurship come together. It is based on the paradigm of Open Innovation 2.0 (OI2.0), which is founded on the Quadruple Helix Model, where Government, Industry, Academia and Society work together to drive change by taking full advantage of the cross-fertilization of ideas. The ECoE as a Digital Innovation Hub (DIH) adopts a two-axis model, where the vertical axis consists of three Thematic Clusters for sustained excellence in research of the ECoE in the domains of Atmosphere and Climate, Resilient Societies and Big Earth Data Management, while the horizontal axis is built around four functional areas, namely: Infrastructure, Research, Education, and Entrepreneurship. The ECoE will focus on five application areas, which include Climate Change Monitoring, Water Resource Management, Disaster Risk Reduction, Access to Energy and Big EO Data Analytics. This structure is expected to leverage the existing regional capacities and advance the excellence by creating new programs and research, thereby establishing the ECoE as a worldclass centre capable of enabling innovation and research competence in Earth Observation, actively participating in Europe, the EMMENA region and the global Earth Observation arena. The partners of the EXCELSIOR consortium include the Cyprus University of Technology as the Coordinator, the German Aerospace Center (DLR), the Leibniz Institute for Tropospheric Research (TROPOS), the National Observatory of Athens (NOA) and the Department of Electronic Communications, Deputy Ministry of Research, Innovation and Digital Policy

Semi-Interpenetrating Polymer Networks with Predefined Architecture for Metal Ion Fluorescence Monitoring

The development of new synthetic approaches for the preparation of efficient 3D luminescent chemosensors for transition metal ions receives considerable attention nowadays, owing to the key role of the latter as elements in biological systems and their harmful environmental effects when present in aquatic media. In this work, we describe an easy and versatile synthetic methodology that leads to the generation of nonconjugated 3D luminescent semi-interpenetrating amphiphilic networks (semi-IPN) with structure-defined characteristics. More precisely, the synthesis involves the encapsulation of well-defined poly(9-anthrylmethyl methacrylate) (pAnMMA) (hydrophobic, luminescent) linear polymer chains within a covalent poly(2-(dimethylamino)ethyl methacrylate) (pDMAEMA) hydrophilic polymer network, derived via the 1,2-bis-(2-iodoethoxy)ethane (BIEE)-induced crosslinking process of well-defined pDMAEMA linear chains. Characterization of their fluorescence properties demonstrated that these materials act as strong blue emitters when exposed to UV irradiation. This, combined with the presence of the metal-binding tertiary amino functionalities of the pDMAEMA segments, allowed for their applicability as sorbents and fluorescence chemosensors for transition metal ions (Fe3+, Cu2+) in solution via a chelation-enhanced fluorescence-quenching effect promoted within the semi-IPN network architecture. Ethylenediaminetetraacetic acid (EDTA)-induced metal ion desorption and thus material recyclability has been also demonstrated

The epigenetic modifier Fam208a is required to maintain epiblast cell fitness

Abstract Gastrulation initiates with the formation of the primitive streak, during which, cells of the epiblast delaminate to form the mesoderm and definitive endoderm. At this stage, the pluripotent cell population of the epiblast undergoes very rapid proliferation and extensive epigenetic programming. Here we show that Fam208a, a new epigenetic modifier, is essential for early post-implantation development. We show that Fam208a mutation leads to impaired primitive streak elongation and delayed epithelial-to-mesenchymal transition. Fam208a mutant epiblasts had increased expression of p53 pathway genes as well as several pluripotency-associated long non-coding RNAs. Fam208a mutants exhibited an increase in p53-driven apoptosis and complete removal of p53 could partially rescue their gastrulation block. This data demonstrates a new in vivo function of Fam208a in maintaining epiblast fitness, establishing it as an important factor at the onset of gastrulation when cells are exiting pluripotency

Remodeling of extracellular matrix due to solid stress accumulation during tumor growth

<div><p></p><p>Solid stresses emerge as the expanding tumor displaces and deforms the surrounding normal tissue, and also as a result of intratumoral component interplay. Among other things, solid stresses are known to induce extensive extracellular matrix synthesis and reorganization. In this study, we developed a mathematical model of tumor growth that distinguishes the contribution to stress generation by collagenous and non-collagenous tumor structural components, and also investigates collagen fiber remodeling exclusively due to solid stress. To this end, we initially conducted <i>in vivo</i> experiments using an orthotopic mouse model for breast cancer to monitor primary tumor growth and derive the mechanical properties of the tumor. Subsequently, we fitted the mathematical model to experimental data to determine values of the model parameters. According to the model, intratumoral solid stress is compressive, whereas extratumoral stress in the tumor vicinity is compressive in the radial direction and tensile in the periphery. Furthermore, collagen fibers engaged in stress generation only in the peritumoral region, and not in the interior where they were slackened due to the compressive stress state. Peritumoral fibers were driven away from the radial direction, tended to realign tangent to the tumor–host interface, and were also significantly stretched by tensile circumferential stresses. By means of this remodeling, the model predicts that the tumor is enveloped by a progressively thickening capsule of collagen fibers. This prediction is consistent with long-standing observations of tumor encapsulation and histologic sections that we performed, and it further corroborates the expansive growth hypothesis for the capsule formation.</p></div