Publications

Cells can adapt their active contractile properties to switch between dynamical migratory states and static homeostasis. Collective tissue surface tension, generated among others by the cortical contractility of single cells, can keep cell clusters compact, while a more bipolar, anisotropic contractility is predominantly used by mesenchymal cells to pull themselves into the extracellular matrix (ECM). Here, we investigate how these two contractility modes relate to cancer cell escape into the ECM. We compare multicellular spheroids from a panel of breast cancer cell lines with primary tumor explants from breast and cervical cancer patients by measuring matrix contraction and cellular spreading into ECM mimicking collagen matrices. Our results in spheroids suggest that tumor aggressiveness is associated with elevated contractile traction and reduced active tissue surface tension, allowing cancer cell escape. We show that it is not a binary switch but rather the interplay between these two contractility modes that is essential during this process. We provide further evidence in patient-derived tumor explants that these two contractility modes impact cancer cells' ability to leave cell clusters within a primary tumor. Our results indicate that cellular contractility is an essential factor during the formation of metastases and thus may be suitable as a prognostic criterion for the assessment of tumor aggressiveness.

JTD Keywords: Breast-cancer, Disease, Emt, Forces, Hypothesis, Intercellular-adhesion, Myoepithelial cell, Stiffness, Wetting transition

Factor XII (FXII) is a zymogen present in blood that tends to adsorb onto the surfaces of blood-contacting medical devices. Once adsorbed, it becomes activated, initiating a cascade of enzymatic reactions that lead to surface-induced coagulation. This process is characterized by multiple redundancies, making it extremely challenging to prevent clot formation and preserve the properties of the surface. In this study, a novel modulatory coating system based on C1-esterase inhibitor (C1INH) functionalized polymer brushes, which effectively regulates the activation of FXII is proposed. Using surface plasmon resonance it is demonstrated that this coating system effectively repels blood plasma proteins, including FXII, while exhibiting high activity against activated FXII and plasma kallikrein under physiological conditions. This unique property enables the modulation of FXII activation without interfering with the overall hemostasis process. Furthermore, through dynamic Chandler loop studies, it is shown that this coating significantly improves the hemocompatibility of polymeric surfaces commonly used in medical devices. By addressing the root cause of contact activation, the synergistic interplay between the antifouling polymer brushes and the modulatory C1INH is expected to lay the foundation to enhance the hemocompatibility of medical device surfaces.© 2023 The Authors. Macromolecular Bioscience published by Wiley-VCH GmbH.

JTD Keywords: adsorption, binding, c1-esterase-inhibitor, coatings, contact activation, factor-xii, fxii activation, hemocompatibility, hemocompatible surface modification, heparin, polymer brushes, system, thrombosis, Adsorption, Anticoagulation, Antifouling agent, Article, Beta-fxiia, Biocompatibility, Blood, Blood clotting, Blood clotting factor 12, Blood clotting factor 12a, Blood clotting factor 12a inhibitor, Blood coagulation, C1-esterase-inhibitor, Cell activation, Chemical activation, Coagulation, Coating (procedure), Complement component c1s inhibitor, Complement system, Controlled study, Dendrimers, Enzyme immobilization, Enzymes, Erythrocyte, Esters, Factor xii, Factor xii activation, Factor xiia, Fibrin deposition, Functional polymers, Fxii activation, Haemocompatibility, Hemocompatibility, Hemocompatible surface modification, Hemostasis, Heparin, Human, Hydrogel, Medical devices, Metabolism, Plasma kallikrein, Plasma protein, Plastic coatings, Platelet count, Polymer, Polymer brushes, Polymerization, Polymers, Property, Root cause, Surface plasmon resonance, Surface property, Surface reactions, Surface-modification, Thrombocyte adhesion, Β-fxiia

Extracellular matrix (ECM) tumorigenic alterations resulting in high matrix deposition and stiffening are hallmarks of adenocarcinomas and are collectively defined as desmoplasia. Here, we thoroughly analysed primary prostate cancer tissues obtained from numerous patients undergoing radical prostatectomy to highlight reproducible structural changes in the ECM leading to the loss of the glandular architecture. Starting from patient cells, we established prostate cancer tumoroids (PCTs) and demonstrated they require TGF-beta signalling pathway activity to preserve phenotypical and structural similarities with the tissue of origin. By modulating TGF-beta signalling pathway in PCTs, we unveiled its role in ECM accumulation and remodelling in prostate cancer. We also found that TGF-beta-induced ECM remodelling is responsible for the initiation of prostate cell epithelial-tomesenchymal transition (EMT) and the acquisition of a migratory, invasive phenotype. Our findings highlight the cooperative role of TGF-beta signalling and ECM desmoplasia in prompting prostate cell EMT and promoting tumour progression and dissemination.

JTD Keywords: Cancer, Cancer,tumour,extracellular matrix (ecm),tumoroids,prostate,epithelial-to-mesenchymal transition (emt),transforming growth factor (tgf, Cell line, tumor, Epithelial-mesenchymal transition, Epithelial-to-mesenchymal transition (emt), Extracellular matrix, Extracellular matrix (ecm), Humans, Male, Mesenchymal transition emt,tenascin-c,cell-migration,quality-control,expressio, Prostate, Prostatic neoplasms, Transforming growth factor (tgf)-β, Transforming growth factor beta, Tumoroids, Tumour

There has been a renewed interest in the potential use of psychedelics for the treatment of psychiatric conditions. Nevertheless, little is known about the mechanism of action and molecular pathways influenced by ayahuasca use in humans. Therefore, for the first time, our study aims to investigate the human metabolomics signature after consumption of a psychedelic, ayahuasca, and its connection with both the psychedelic-induced subjective effects and the plasma concentrations of ayahuasca alkaloids. Plasma samples of 23 individuals were collected both before and after ayahuasca consumption. Samples were analysed through targeted metabolomics and further integrated with subjective ratings of the ayahuasca experience (i.e., using the 5-Dimension Altered States of Consciousness Rating Scale [ASC]), and plasma ayahuasca-alkaloids using integrated network analysis. Metabolic pathways enrichment analysis using diffusion algorithms for specific KEGG modules was performed on the metabolic output. Compared to baseline, the consumption of ayahuasca increased N-acyl-ethanolamine endocannabinoids, decreased 2-acyl-glycerol endocannabinoids, and altered several large-neutral amino acids (LNAAs). Integrated network results indicated that most of the LNAAs were inversely associated with 9 out of the 11 subscales of the ASC, except for tryptophan which was positively associated. Several endocannabinoids and hexosylceramides were directly associated with the ayahuasca alkaloids. Enrichment analysis confirmed dysregulation in several pathways involved in neurotransmission such as serotonin and dopamine synthesis. In conclusion, a crosstalk between the circulating LNAAs and the subjective effects is suggested, which is independent of the alkaloid concentrations and provides insights into the specific metabolic fingerprint and mechanism of action underlying ayahuasca experiences. © 2022 The Authors

JTD Keywords: anxiety, ayahuasca, dimethyltryptamine, integrative network analysis, metabolism, metabolomics, psychedelics, rats, subjective effects, system, tryptophan, Ayahuasca, Dimethyltryptamine, Integrative network analysis, Metabolomics, Psychedelics, Serotonin 5-ht2a, Subjective effects

During development, organs reach precise shapes and sizes. Organ morphology is not always obtained through growth; a classic counterexample is the condensation of the nervous system during Drosophila embryogenesis. The mechanics underlying such condensation remain poorly understood. Here, we characterize the condensation of the embryonic ventral nerve cord (VNC) at both subcellular and tissue scales. This analysis reveals that condensation is not a unidirectional continuous process but instead occurs through oscillatory contractions. The VNC mechanical properties spatially and temporally vary, and forces along its longitudinal axis are spatially heterogeneous. We demonstrate that the process of VNC condensation is dependent on the coordinated mechanical activities of neurons and glia. These outcomes are consistent with a viscoelastic model of condensation, which incorporates time delays and effective frictional interactions. In summary, we have defined the progressive mechanics driving VNC condensation, providing insights into how a highly viscous tissue can autonomously change shape and size.

JTD Keywords: actomyosin, central nervous system, drosophila, glia, mechanics, morphogenesis, neuron, ventral nerve cord, Actomyosin, Animals, Central nervous system, Collagen-iv, Contraction, Drosophila, Embryonic development, Forces, Gene, Glia, Glial-cells, Mechanics, Migration, Morphogenesis, Neuroglia, Neuron, Neurons, Quantification, System, Tissue, Ventral nerve cord, Viscolelastic model