Physical Aspects of Local Solid Tumor Growth

Krebszellen haben gemeinsame Eigenschaften, wie unbegrenztes Wachstumspotential und die Vermeidung von Apoptose. Krebs kann als systemische Erkrankung angesehen werden und es reicht daher nicht aus, molekulare Details von Krebs zu verstehen, sondern auch emergente physikalische Eigenschaften von Krebs auf mehreren Größenskalen von Genen über Zellen bis hin zu Geweben. Diese Arbeit konzentriert sich auf physikalische Eigenschaften die an der Krebsprogression, der Migration von Krebszellen und dem Krebswachstum beteiligt sind. Die Migration von Krebszellen führt zur Fähigkeit zur Metastasierung, der häufigsten Ursache für krebsbedingten Tod. Der Schlüssel zu diesem Prozess ist die Verformbarkeit von Krebszellen beim Durchqueren der dichten Mikroumgebung aus extrazellulärer Matrix und anderen Zellen. Der genaue Beitrag des Aktin- und Mikrotubuli-Netzwerks zur zellulären elastischen Verformung und Entspannung ist wichtig und wurde untersucht. Ein wichtiges Ergebnis ist, dass bei kleinen Verformungen (5%) Aktin-Filamente und Mikrotubuli gleichermaßen zur Zellverformung und -relaxation beitragen. So sind die Mikrotubuli für die Migration in Mikroumgebungen von größerer Bedeutung, als es die aktuelle Literatur vermuten lässt. Ein initial gebildeter bösartiger Tumor tritt typischerweise in eine Wachstumsphase ein, in der das umgebende Gewebe verdrängt und eingedrungen wird. Für ein optimales klinisches Behandlungsergebnis sollte der Primärtumor so gut wie möglich entfernt werden, was die genaue Erkennung der Tumorfront und die Identifizierung der Gewebe mit dem Risiko einer Krebsinfiltration beinhaltet. In dieser Arbeit werden natürliche Hindernisse und Grenzen für das Krebswachstum, wie z.B. Fasziengewebsgrenzen oder Gewebekompartimentgrenzen, basierend auf klinischen Daten von Gebärmutterhalskrebs analysiert, die aus der pathologischen Untersuchung von chirurgisch resezierten Tumoren von 518 Patienten gewonnen wurden. Die Wachstumsgrenzen wurden als embryonale Gewebeentwicklungsgrenzen identifiziert und betonen, dass Krebs Entwicklungsmerkmale aufweist, die häufig in der Embryogenese vorkommen. Das gefundene Tumorwachstumsmuster und die -form widersprechen dem das das vorherrschende Dogma der isotropen Tumorwachstum, welches der chirurgischen Tumorresektion und Strahlentherapie zugrunde liegt. Die Tumorform-Distribution weist starke Abweichungen von sphärischer Symmetrie auf, was darauf hindeutet, dass Tumore durch entwicklungsbiologische Kompartimente und deren Kompartimentsgrenzen begrenzt und geformt werden. Computersimulationen liefern auch den Nachweis, dass die klinisch gefundene Tumorinfiltrationswahrscheinlichkeit von Geweben nicht auf der metrischen Entfernung des gefährdeten Gewebes zum Gewebe der Tumorherkunft basiert, sondern auf der ontogenetischen Verwandtschaft der Gewebe

Schaltbare Moleküle auf Oberflächen - das Plattform Konzept

Im Rahmen dieser Arbeit konnte ein neues Konzept zur Funktionalisierung von Goldoberflächen mit schaltbaren Molekülen realisiert werden. Azobenzole benötigen für die lichtinduzierte trans/cis-Isomerisierung auf Oberflächen einen gewissen Freiraum, damit der Schaltprozess stattfinden kann. Bei Verwendung von alkanthiolfunktionalisierten Azobenzolen bilden sich zwar selbstorganisierende Monoschichten (SAMs) aus, jedoch ist der Schaltprozess aufgrund der dichten Packung der Moleküle sterisch gehindert. Um dies zu vermeiden, wurde das Plattform-Konzept entwickelt. Triazatriangulenium Ionen wurden als raumgreifende, molekulare Plattformen verwendet, die hexagonal geordnete Monoschichten auf Au(111) bilden. Es wurde eine Vielzahl an azobenzolsubstituierten Derivaten synthetisiert und untersucht. Auf Oberflächen bilden diese Derivate ebenfalls wohlgeordnete Monoschichten aus. Dabei stehen die Azobenzol-Substituenten senkrecht zur Ebene und in einem wohldefinierten intermolekularen Abstand zueinander. Durch Variation der Länge der Seitenketten der Plattform kann dieser Abstand eingestellt werden und ist ausreichend, um den Schaltprozess zu gewährleisten

Jamming in Embryogenesis and Cancer Progression

The ability of tissues and cells to move and rearrange is central to a broad range of diverse biological processes such as tissue remodeling and rearrangement in embryogenesis, cell migration in wound healing, or cancer progression. These processes are linked to a solidlike to fluid-like transition, also known as unjamming transition, a not rigorously defined framework that describes switching between a stable, resting state and an active, moving state. Various mechanisms, that is, proliferation and motility, are critical drivers for the (un) jamming transition on the cellular scale. However, beyond the scope of these fundamental mechanisms of cells, a unifying understanding remains to be established. During embryogenesis, the proliferation rate of cells is high, and the number density is continuously increasing, which indicates number-density-driven jamming. In contrast, cells have to unjam in tissues that are already densely packed during tumor progression, pointing toward a shape-driven unjamming transition. Here, we review recent investigations of jamming transitions during embryogenesis and cancer progression and pursue the question of how they might be interlinked. We discuss the role of density and shape during the jamming transition and the different biological factors driving it

Actin and microtubule networks contribute differently to cell response for small and large strains

Cytoskeletal filaments provide cells with mechanical stability and organization. The main key players are actin filaments and microtubules governing a cell’s response to mechanical stimuli. We investigated the specific influences of these crucial components by deforming MCF-7 epithelial cells at small(\u845% deformation) and large strains(>5% deformation). To understand specific contributions of actin filaments and microtubules, we systematically studied cellular responses after treatment with cytoskeleton influencing drugs. Quantification with the microfluidic optical stretcher allowed capturing the relative deformation and relaxation of cells under different conditions. We separated distinctive deformational and relaxational contributions to cell mechanics for actin and microtubule networks for two orders of magnitude of drug dosages. Disrupting actin filaments via latrunculin A, for instance, revealed a strain-independent softening. Stabilizing these filaments by treatment with jasplakinolide yielded cell softening for small strains but showed no significant change at large strains. In contrast, cells treated with nocodazole to disrupt microtubules displayed a softening at large strains but remained unchanged at small strains. Stabilizing microtubules within the cells via paclitaxel revealed no significant changes for deformations at small strains, but concentration-dependent impact at large strains. This suggests that for suspended cells, the actin cortex is probed at small strains, while at larger strains; the whole cell is probed with a significant contribution from the microtubule

Differences in cortical contractile properties between healthy epithelial and cancerous mesenchymal breast cells

Cell contractility is mainly imagined as a force dipole-like interaction based on actin stress fibers that pull on cellular adhesion sites. Here, we present a different type of contractility based on isotropic contractions within the actomyosin cortex. Measuring mechanosensitive cortical contractility of suspended cells among various cell lines allowed us to exclude effects caused by stress fibers. We found that epithelial cells display a higher cortical tension than mesenchymal cells, directly contrasting to stress fiber-mediated contractility. These two types of contractility can even be used to distinguish epithelial from mesenchymal cells. These findings from a single cell level correlate to the rearrangement effects of actomyosin cortices within cells assembled in multicellular aggregates. Epithelial cells form a collective contractile actin cortex surrounding multicellular aggregates and further generate a high surface tension reminiscent of tissue boundaries. Hence, we suggest this intercellular structure as to be crucial for epithelial tissue integrity. In contrast, mesenchymal cells do not form collective actomyosin cortices reducing multicellular cohesion and enabling cell escape from the aggregates

Self-assembly of triazatriangulenium-based functional adlayers on Au(111) surfaces

Detailed scanning tunneling microscopy studies of the attachment of freestanding molecular functions to Au(111) surfaces via self-assembly of functional molecules based on triazatriangulenium platforms are presented. As shown for molecules with side chains of different length and phenyl, azobenzyl, or azobenzyl derivatives with different terminal groups (iodo, cyano, or dimethyl) as functional units, this approach allows the preparation of very stable, hexagonally ordered adlayers. The intermolecular spacings in these adlayers are independent of the attached functions with the latter being orientated perpendicular to the Au surface. Due to their open structure, adlayers of platforms with attached functional groups exhibit a tendency towards bilayer formation, which can be suppressed by derivatization with appropriate terminal groups

Detecting heterogeneity in and between breast cancer cell lines

Cellular heterogeneity in tumor cells is a well-established phenomenon. Genetic and phenotypic cell-to-cell variability have been observed in numerous studies both within the same type of cancer cells and across different types of cancers. Another known fact for metastatic tumor cells is that they tend to be softer than their normal or non-metastatic counterparts. However, the heterogeneity of mechanical properties in tumor cells are not widely studied. Here we analyzed single-cell optical stretcher data with machine learning algorithms on three different breast tumor cell lines and show that similar heterogeneity can also be seen in mechanical properties of cells both within and between breast tumor cell lines. We identified two clusters within MDA-MB-231 cells, with cells in one cluster being softer than in the other. In addition, we show that MDA-MB-231 cells and MDA-MB-436 cells which are both epithelial breast cancer cell lines with a mesenchymal-like phenotype derived from metastatic cancers are mechanically more different from each other than from non-malignant epithelial MCF-10A cells. Since stiffness of tumor cells can be an indicator of metastatic potential, this result suggests that metastatic abilities could vary within the same monoclonal tumor cell line.https://doi.org/10.1186/s41236-020-0010-

DEDICATE: proposal for a conceptual framework to develop dementia-friendly Integrated eCare support

Background: Evidence shows that the implementation of Information and Communication Technologies (ICT) enabled services supporting integrated dementia care represents an opportunity that faces multi-pronged challenges. First, the provision of dementia support is fragmented and often inappropriate. Second, available ICT solutions in this field do not address the full spectrum of support needs arising across an individual’s whole dementia journey. Current solutions fail to harness the potential of available validated e-health services, such as telehealth and telecare, for the purposes of dementia care. Third, there is a lack of understanding of how viable business models in this field can operate. The field comprises both professional and non-professional players that interact and have roles to play in ensuring that useful technologies are developed, implemented and used. Methods: Starting from a literature review, including relevant pilot projects for ICT-based dementia care, we define the major requirements of a system able to overcome the limitations evidenced in the literature, and how this system should be integrated in the socio-technical ecosystem characterizing this disease. From here, we define the DEDICATE architecture of such a system, and the conceptual framework mapping the architecture over the requirements. Results: We identified three macro-requirements, namely the need to overcome: deficient technology innovation, deficient service process innovation, and deficient business models innovation. The proposed architecture is a three level architecture in which the center (data layer) includes patients’ and informal caregivers’ preferences, memories, and other personal data relevant to sustain the dementia journey, is connected through a middleware (service layer), which guarantees core IT services and integration, to dedicated applications (application layer) to sustain dementia care (Formal Support Services, FSS), and to existing formal care infrastructures, in order to guarantee care coordination (Care Coordination Services, CCS). Conclusions: The proposed DEDICATE architecture and framework envisages a feasible means to overcome the present barriers by: (1) developing and integrating technologies that can follow the patient and the caregivers throughout the development of the condition, since the early stages in which the patient is able to build up preferences and memories will be used in the later stages to maximise personalization and thereby improve efficacy and usability (technology innovation); (2) guaranteeing the care coordination between formal and informal caregivers, and giving an active yet supported role to the latter (service innovation); and (3) integrating existing infrastructures and care models to decrease the cost of the overall care pathway, by improving system interoperability (business model innovation)

Can integrated care help in meeting the challenges posed on our health care systems by COVID-19? Some preliminary lessons learned from the european VIGOUR project

The COVID-19 pandemic puts health and care systems under pressure globally. This current paper highlights challenges arising in the care for older and vulnerable populations in this context and reflects upon possible perspectives for different systems making use of nested integrated care approaches adapted during the work of the EU-funded project VIGOUR

Can Integrated Care Help in Meeting the Challenges Posed on Our Health Care Systems by COVID-19? Some Preliminary Lessons Learned from the European VIGOUR Project

The COVID-19 pandemic puts health and care systems under pressure globally. This current paper highlights challenges arising in the care for older and vulnerable populations in this context and reflects upon possible perspectives for different systems making use of nested integrated care approaches adapted during the work of the EU-funded project VIGOU