Cell Adhesion Mechanisms Research Articles

Experimental models of fibrosis

Fibrosis, as a pathological process, is characterized by excessive accumulation of extracellular matrix and can affect various organs and tissues, including the lungs, liver, heart and kidneys, leading to serious morbidity and poor quality of life. The main mechanisms of fibrosis are disturbances in cellular signaling pathways, their regulation, interaction, including disturbances in the exchange of cellular regulatory signals, impaired mechanisms of cell adhesion, and changes in the extracellular matrix. All this makes the search for new agents with antifibrotic activity to be urgent. The review examines the basic mechanisms of the development of fibrosis with an emphasis on experimental models, as well as the potential and limitations of experimental models of fibrosis in the context of further search and study of new drugs with antifibrotic activity.

Proteomic biomarkers related to obesity in heart failure with reduced ejection fraction and their associations with outcome.

Heart failure (HF) pathophysiology in patients with obesity may be distinct. To study these features, we identified obesity-related biomarkers from 4210 circulating proteins in patients with HF with reduced ejection fraction (HFrEF) and examined associations of these proteins with HF prognosis and biological mechanisms. In 373 patients with trimonthly blood sampling during a median follow-up of 2.1 (25th-75th percentile: 1.1-2.6) years, we applied an aptamer-based multiplex approach measuring 4210 proteins in baseline samples and the last two samples before study end. Associations between obesity (BMI > 30 kg/m2) and baseline protein levels were analyzed. Subsequently, associations of serially measured obesity-related proteins with biological mechanisms and the primary endpoint (PEP; composite of cardiovascular mortality, HF hospitalization, left ventricular assist device implantation, and heart transplantation) were examined. Obesity was identified in 26% (96/373) of patients. A total of 30% (112/373) experienced a PEP (with obesity: 26% [25/96] vs. without obesity: 31% [87/277]). A total of 141/4210 proteins were linked to obesity, reflecting mechanisms of neuron projection development, cell adhesion, and muscle cell migration. A total of 50/141 proteins were associated with the PEP, of which 12 proteins related to atherosclerosis or hypertrophy provided prognostic information beyond clinical characteristics, N-terminal pro-B-type natriuretic peptide, and high-sensitivity troponin T. Patients with HFrEF and obesityshow distinct proteomic profiles compared to patients with HFrEF without obesity. Obesity-related proteins are independently associated with HF outcome. These proteins carry potential to improve management of obesity-related HF and could be leads for future research.

Arrhythmogenic cardiomyopathy-related cadherin variants affect desmosomal binding kinetics

Cadherins are calcium dependent adhesion proteins that establish and maintain the intercellular mechanical contact by bridging the gap between adjacent cells. Desmoglein-2 (Dsg2) and desmocollin-2 (Dsc2) are tissue specific cadherin isoforms of the cell-cell contact in cardiac desmosomes. Mutations in the DSG2-gene and in the DSC2-gene are related to arrhythmogenic right ventricular cardiomyopathy (ARVC) a rare but severe heart muscle disease. Here, several possible homophilic and heterophilic binding interactions of wild-type Dsg2, wild-type Dsc2, as well as one Dsg2- and two Dsc2-variants, each associated with ARVC, are investigated. Using single molecule force spectroscopy (SMFS) with atomic force microscopy (AFM) and applying Jarzynski's equality the kinetics and thermodynamics of Dsg2/Dsc2 interaction can be determined. The free energy landscape of Dsg2/Dsc2 dimerization exposes a high activation energy barrier, which is in line with the proposed strand-swapping binding motif. Although the binding motif is not affected by any of the mutations, the binding kinetics of the interactions differ significantly from the wild-type. While wild-type cadherins exhibit an average complex lifetime of approx. 0.3 s interactions involving a variant consistently show - lifetimes that are substantially larger. The lifetimes of the wild-type interactions give rise to the picture of a dynamic adhesion interface consisting of continuously dissociating and (re)associating molecular bonds, while the delayed binding kinetics of interactions involving an ARVC-associated variant might be part of the pathogenesis. Our data provide a comprehensive and consistent thermodynamic and kinetic description of cardiac cadherin binding, allowing detailed insight into the molecular mechanisms of cell adhesion.

Molecular Crosstalk Between Adherens Junction Proteins, E-cadherin and Nectin-4

Cell-cell junctions formed by the association of cell adhesion molecules facilitate physiological events necessary for growth and development of multicellular organisms. Among them, cadherins and nectins organize and assemble to form adherens junction, which thereby mechanically couples interacting cells. A detailed understanding of the crosstalk involving these cell adhesion molecules is fundamental to the study of the various developmental processes. Although, cadherins and nectins can recruit each other in the adherens junction through an interplay of cytoplasmic adaptor molecules, here, we report a direct interaction between N-terminal extracellular domains of E-cadherin and nectin-4 as demonstrated by surface plasmon resonance (SPR) and Atomic Force Microscopy (AFM)-based single molecule force spectroscopy (SMFS). Kinetic studies using SPR demonstrate the binding between the ectodomains of E-cadherin and nectin-4 with a KD of 3.7 ± 0.7 µM and KD of 5.4 ± 0.2 µM (reciprocal experiment). AFM-based SMFS experiments also support interaction between the ectodomains of E-cadherin and nectin-4 with the koff value of 31.48 ± 1.53 s−1 and the lifetime of the complex of 0.036 ± 0.0026 s. We thus propose a cell adhesion mechanism mediated by E-cadherin and nectin-4, which can have functional significance in early embryogenesis as evident from the expression pattern of both the proteins during early development.

Phytoconstituent-derived zingerone nanoparticles disrupt the cell adhesion mechanism and suppress cell motility in melanoma B16F10 cells

Combining phytochemicals and nanotechnology to improve the unfavorable innate properties of phytochemicals and develop them into potent nanomedicines to enhance antitumor efficacy has become a novel strategy for cancer chemoprevention. Melanoma is the most aggressive, metastatic, and deadly disease of the primary cutaneous neoplasms. In this study, we fabricated phytoconstituent-derived zingerone nanoparticles (NPs) and validated their effects on cell adhesion and motility in melanoma B16F10 cells. Our data indicated that zingerone NPs significantly induced cytotoxicity and anti-colony formation and inhibited cell migration and invasion. Moreover, zingerone NPs dramatically interfered with the cytoskeletal reorganization and markedly delayed the period of cell adhesion. Our results also revealed that zingerone NPs-mediated downregulation of MMPs (matrix metalloproteinases) activity is associated with inhibiting cell adhesion and motility. We further evaluated the effects of zingerone NPs on Src/FAK /Paxillin signaling, our data showed that zingerone NPs significantly inhibited the protein activities of Src, FAK, and Paxillin, indicating that they play important roles in zingerone NP-mediated anti-motility and anti-invasion in melanoma cells. Accordingly, the phytoconstituent-zingerone NPs can strengthen the inhibition of tumor growth, invasion, and metastasis in malignant melanoma. Altogether, these multi-pharmacological benefits of zingerone NPs will effectively achieve the purpose of melanoma prevention and invasion inhibition.

Significance of a minor pilin PilV in biofilm cohesion of Geobacter sulfurreducens

Bacterial adhesion plays a vital role in forming and shaping the structure of electroactive biofilms that are essential for the performance of bioelectrochemical systems (BESs). Type IV pili are known to mediate cell adhesion in many Gram-negative bacteria, but the mechanism of pili-mediated cell adhesion of Geobacter species on anode surface remains unclear. Herein, a minor pilin PilV2 was found to be essential for cell adhesion ability of Geobacter sulfurreducens since the lack of pilV2 gene depressed the cell adhesion capability by 81.2% in microplate and the anodic biofilm density by 23.1 % at −0.1 V and 37.7 % at −0.3 V in BESs. The less cohesiveness of mutant biofilms increased the charge transfer resistance and biofilm resistance, which correspondingly lowered current generation of the pilV2-deficient strain by up to 63.2 % compared with that of the wild-type strain in BESs. The deletion of pilV2 posed an insignificant effect on the production of extracellular polysaccharides, pili, extracellular cytochromes and electron shuttles that are involved in biofilm formation or extracellular electron transfer (EET) process. This study demonstrated the significance of pilV2 gene in cell adhesion and biofilm formation of G. sulfurreducens, as well as the importance of pili-mediated adhesion for EET of electroactive biofilm.

MiR-194-3p regulates epithelial-mesenchymal transition in embryonic epicardial cells via p120/β-catenin signaling.

The epicardium is integral to cardiac development and facilitates endogenous heart regeneration and repair. While miR-194-3p is associated with cellular migration and invasion, its impact on epicardial cells remains uncharted. In this work we use gain-of-function and loss-of-function methodologies to investigate the function of miR-194-3p in cardiac development. We culture embryonic epicardial cells in vitro and subject them to transforming growth factor β (TGF-β) treatment to induce epithelial-mesenchymal transition (EMT) and monitor miR-194-3p expression. In addition, the effects of miR-194-3p mimics and inhibitors on epicardial cell development and changes in EMT are investigated. To validate the binding targets of miR-194-3p and its ability to recover the target gene-phenotype, we produce a mutant vector p120-catenin-3'UTR-MUT. In epicardial cells, TGF-β-induced EMT results in a notable overexpression of miR-194-3p. The administration of miR-194-3p mimics promotes EMT, which is correlated with elevated levels of mesenchymal markers. Conversely, miR-194-3p inhibitor attenuates EMT. Further investigations reveal a negative correlation between miR-194-3p and p120-catenin, which influences β-catenin level in the cell adhesion pathway. The suppression of EMT caused by the miR-194-3p inhibitor is balanced by silencing of p120-catenin. In conclusion, miR-194-3p directly targets p120-catenin and modulates its expression, which in turn alters β-catenin expression, critically influencing the EMT process in the embryonic epicardial cells via the cell adhesion mechanism.

Abstract 5512: Cerebral endothelial FAK paradoxically inhibits brain metastasis in vivo

Abstract Introduction: In cancer metastasis in the trunk, the secreted proteins from tumors, such as VEGFs and TNF-α, activate focal adhesion kinase (FAK) in vascular endothelial cells (VECs). The activated FAK promotes VE-cadherin phosphorylation and the expression of cell adhesion molecules, and it facilitates the extravasation of cancer cells. In the cerebral blood vessels, the VECs maintain very strong cell adhesion supported by the surrounding pericytes and astrocytes. The strong barrier of cerebral VECs is called the blood-brain barrier (BBB) and is regulated differently from trunk VECs. Although the role of FAK in trunk metastasis is shown in many studies, its importance in brain metastasis is not verified. In this study, we focused on the role of the cerebral endothelial FAK and compared the role of FAK in brain metastasis with that in trunk metastasis. Methods: We generated tamoxifen-inducible VEC-specific FAK knockout (FAK-cKO) mice (VEcad-CreERT2; Ptk2-flox/flox) and brain metastatic (BrM) cell lines of Ex3LL (murine lung cancer cell line). We intracardially injected BrM cells of Ex3LL into the FAK-cKO mice and analyzed the tumor development using in vivo bioluminescence imaging and a CUBIC tissue clearing system. We also analyzed the intracranially injected mice of the parental and BrM cell lines to evaluate the tumor angiogenesis, which is reported to be promoted by the endothelial FAK. Results: Although FAK-cKO in VECs has been reported to inhibit lung metastasis, brain metastasis was accelerated in FAK-cKO mice compared with control mice. The number of brain metastatic sites increased in FAK-cKO mice, but there was no difference in the individual tumor size. It suggests that the brain metastasis was promoted by FAK-cKO, but that the proliferation of brain metastasis was not promoted by FAK-cKO. Blood vessel density was decreased with irregular shape in the brain tumors of FAK-cKO mice, suggesting that the angiogenesis was inhibited by FAK-cKO. It indicates that the angiogenic function of endothelial FAK in the brain vasculature was not different from that in the trunk. Conclusion: FAK-cKO in VECs exacerbated the brain metastasis of the BrM cells although it has been reported to inhibit the metastasis in the trunk. FAK-cKO in VECs decreased tumor angiogenesis both in the brain and the trunk. It suggests that the regulatory mechanism of cell adhesion and the FAK function in the brain vasculature is partly different from that in the other organs in the body trunk. We need further investigation to elucidate the function of endothelial FAK in brain metastasis. Citation Format: Shoko Noda-Narita, Atsu Aiba. Cerebral endothelial FAK paradoxically inhibits brain metastasis in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5512.

Host association and intracellularity evolved multiple times independently in the Rickettsiales

The order Rickettsiales (Alphaproteobacteria) encompasses multiple diverse lineages of host-associated bacteria, including pathogens, reproductive manipulators, and mutualists. Here, in order to understand how intracellularity and host association originated in this order, and whether they are ancestral or convergently evolved characteristics, we built a large and phylogenetically-balanced dataset that includes de novo sequenced genomes and a selection of published genomic and metagenomic assemblies. We perform detailed functional reconstructions that clearly indicates “late” and parallel evolution of obligate host-association in different Rickettsiales lineages. According to the depicted scenario, multiple independent horizontal acquisitions of transporters led to the progressive loss of biosynthesis of nucleotides, amino acids and other metabolites, producing distinct conditions of host-dependence. Each clade experienced a different pattern of evolution of the ancestral arsenal of interaction apparatuses, including development of specialised effectors involved in the lineage-specific mechanisms of host cell adhesion and/or invasion.

Modeling the evolution of membrane during cell adhesion on the nanostructured substrate

Using nanostructured substrates for enhancing cell adhesion is an important method. However, the physical mechanism of cell adhesion on nanostructured substrate is not well understood yet, particularly the evolution process of membrane during cell adhesion. Here, we propose an analytical model to study quantitatively the evolution of membrane during adhesion process on the nanostructured substrate. The effects of substrate surface topography, receptor-ligand binding, substrate property and membrane property were investigated. We found a small nanopillar radius, low nanopillar density, large binding rate, large receptor density, low non-specific energy, or large stretching modulus can result in a large adhesion rate and a large adhesion depth. Besides, the evolution of membrane on truncated nanocone arrays was also studied by the model. The theoretical results are in good agreement with the experimental observations, which implied that our studies can provide a useful guide to control cell adhesion process and cell motion on nanostructured substrates.

Modeling evolution of cell morphology under stretching.

The mechanical stimulation of cells from the surrounding environment is an important life activity. However, there has been a lack of dynamically quantitative analysis of cell morphology under mechanical stimulations. A theoretical model for the evolution of cell morphology under stretching is proposed by analyzing the transformation between cell deformation energy and adhesion energy. The images of the evolution show that detachment of the adhesion membrane or re-adhesion of the cell, causes a decrease or increase of the adhesion area, respectively. In addition to the stretching amplitude and velocity, we found that the duration of the stretching stage and the no stretching stage can affect the cell morphology during cyclic stretching. The theoretical model explains some counter-intuitive experimental results and provides many quantitative insights into understanding the physical mechanisms of cell adhesion under stretching. This study can provide a useful guide to control cell adhesion under mechanical stimulations.

Priming chondrocytes during expansion alters cell behavior and improves matrix production in 3D culture

ObjectiveCartilage tissue engineering strategies that use autologous chondrocytes require in vitro expansion of cells to obtain enough cells to produce functional engineered tissue. However, chondrocytes dedifferentiate during expansion culture, limiting their ability to produce chondrogenic tissue and their utility for cell-based cartilage repair strategies. The current study identified conditions that favor cartilage production and the mechanobiological mechanisms responsible for these benefits. DesignChondrocytes were isolated from juvenile bovine knee joints and cultured with (primed) or without (unprimed) a growth factor cocktail. Gene expression, cell morphology, cell adhesion, cytoskeletal protein distribution, and cell mechanics were assessed. Following passage 5, cells were embedded into agarose hydrogels to evaluate functional properties of engineered cartilage. ResultsPriming cells during expansion culture altered cell phenotype and chondrogenic tissue production. Unbiased RNA-sequencing analysis suggested, and experimental studies confirmed, that growth factor priming delays dedifferentiation associated changes in cell adhesion and cytoskeletal organization. Priming also overrode mechanobiological pathways to prevent chondrocytes from remodeling their cytoskeleton to accommodate the stiff, monolayer microenvironment. Passage 1 primed cells deformed less and had lower YAP1 activity than unprimed cells. Differences in cell adhesion, morphology, and cell mechanics between primed and unprimed cells were mitigated by passage 5. ConclusionsPriming suppresses mechanobiologic cytoskeletal remodeling to prevent chondrocyte dedifferentiation, resulting in more cartilage-like tissue-engineered constructs

Differentiation-inducing factor-1 reduces lipopolysaccharide-induced vascular cell adhesion molecule-1 by suppressing mTORC1-S6K signaling in vascular endothelial cells

AimsDifferentiation-inducing factor-1 (DIF-1), a compound in Dictyostelium discoideum, exhibits anti-cancer effects by inhibiting cell proliferation and motility of various mammalian cancer cells in vitro and in vivo. In addition, DIF-1 suppresses lung colony formation in a mouse model, thus impeding cancer metastasis. However, the precise mechanism underlying its anti-metastatic effect remains unclear. In the present study, we aim to elucidate this mechanism by investigating the adhesion of circulating tumor cells to blood vessels using in vitro and in vivo systems. Main methodsMelanoma cells (1.0 × 105 cells) were injected into the tail vein of 8-week-old male C57BL/6 mice after administration of DIF-1 (300 mg/kg per day) and/or lipopolysaccharide (LPS: 2.5 mg/kg per day). To investigate cell adhesion and molecular mechanisms, cell adhesion assay, western blotting, immunofluorescence staining, and flow cytometry were performed. Key findingsIntragastric administration of DIF-1 suppressed lung colony formation. DIF-1 also substantially inhibited the adhesion of cancer cells to human umbilical vein endothelial cells. Notably, DIF-1 did not affect the expression level of adhesion-related proteins in cancer cells, but it did decrease the expression of vascular cell adhesion molecule-1 (VCAM-1) in human umbilical vein endothelial cells by suppressing its mRNA-to-protein translation through inhibition of mTORC1-p70 S6 kinase signaling. SignificanceDIF-1 reduced tumor cell adhesion to blood vessels by inhibiting mTORC1-S6K signaling and decreasing the expression of adhesion molecule VCAM-1 on vascular endothelial cells. These findings highlight the potential of DIF-1 as a promising compound for the development of anti-cancer drugs with anti-metastatic properties.

Influence of tumor mycobiome on cancer pathogenesis (Review).

Cancer tissues harbor a large microbiome. There is growing evidence that the tumor microbiome is significantly correlated with the prognosis of cancer patients, but the exact underlying mechanisms have remained elusive. Although the tumor mycobiome is less abundant than the biome of bacteria, it is prevalent in most cancers in humans. The present review describes in detail the impact of the tumor mycobiome on cancer pathogenesis. The tumor mycobiome promotes tumor progression and metastasis by affecting the human immune system, maintaining a pro-inflammatory environment, producing aflatoxins, attenuating cell adhesion mechanisms and fungal-bacterial interactions. Furthermore, the tumor mycobiome likewise has great potential for cancer prevention, diagnosis and treatment.

Environmental and molecular regulation of asexual reproduction in the sea anemone Nematostella vectensis

Cnidarians exhibit incredible reproductive diversity, with most capable of sexual and asexual reproduction. Here, we investigate factors that influence asexual reproduction in the burrowing sea anemone Nematostella vectensis, which can propagate asexually by transverse fission of the body column. By altering culture conditions, we demonstrate that the presence of a burrowing substrate strongly promotes transverse fission. In addition, we show that animal size does not affect fission rates, and that the plane of fission is fixed along the oral–aboral axis of the polyp. Homeobox transcription factors and components of the TGF β , Notch, and FGF signalling pathways are differentially expressed in polyps undergoing physal pinching suggesting they are important regulators of transverse fission. Gene ontology analyses further suggest that during transverse fission the cell cycle is suppressed, and that cell adhesion and patterning mechanisms are downregulated to promote separation of the body column. Finally, we demonstrate that the rate of asexual reproduction is sensitive to population density. Collectively, these experiments provide a foundation for mechanistic studies of asexual reproduction in Nematostella, with implications for understanding the reproductive and regenerative biology of other cnidarian species.

Cell-scaffold interactions in tissue engineering for oral and craniofacial reconstruction.

Tissue engineering (TE) is critical in oral and craniofacial reconstruction. One of the most popular topics on the biomaterial-based tissue regeneration process may be the interaction between cells and scaffolds. An increasing number of studies have identified the variables affecting cell-scaffold interaction. The creation and investigation of new scaffolds for TE and regenerative medicine based on specific interactions have become possible owing to these findings. This review discusses the effects of various types of scaffold materials on cells in TE. Because the intrinsic properties of scaffolds are essential, the influence of the physical, chemical, mechanical, and biological characteristics of scaffold materials on cell-scaffold interaction that has been discovered in recent research is elaborated in this review. The components carried by scaffolds, the degradation process, and the role of degraded products in cell-scaffold interactions are examined. Further, the roles of cells, including cell types, functions, and adhesion mechanisms, and extracellular matrix are discussed. Finally, the latest research progress on cell-scaffold interactions among various engineered tissues or organs in the oral and craniofacial region is summarized. A deeper understanding of cell-scaffold interactions is anticipated to benefit the development of TE and regenerative medicine.

Bacillus thuringiensis toxins divert progenitor cells toward enteroendocrine fate by decreasing cell adhesion with intestinal stem cells in Drosophila.

Bacillus thuringiensis subsp. kurstaki (Btk) is a strong pathogen toward lepidopteran larvae thanks to specific Cry toxins causing leaky gut phenotypes. Hence, Btk and its toxins are used worldwide as microbial insecticide and in genetically modified crops, respectively, to fight crop pests. However, Btk belongs to the B. cereus group, some strains of which are well known human opportunistic pathogens. Therefore, ingestion of Btk along with food may threaten organisms not susceptible to Btk infection. Here we show that Cry1A toxins induce enterocyte death and intestinal stem cell (ISC) proliferation in the midgut of Drosophila melanogaster, an organism non-susceptible to Btk. Surprisingly, a high proportion of the ISC daughter cells differentiate into enteroendocrine cells instead of their initial enterocyte destiny. We show that Cry1A toxins weaken the E-Cadherin-dependent adherens junction between the ISC and its immediate daughter progenitor, leading the latter to adopt an enteroendocrine fate. Hence, although not lethal to non-susceptible organisms, Cry toxins can interfere with conserved cell adhesion mechanisms, thereby disrupting intestinal homeostasis and endocrine functions.

MiR-142-3p Suppresses Invasion and Adhesion of Mesothelioma Cells by Downregulating ITGAV

Introduction: Malignant mesothelioma is an aggressive cancer associated with asbestos exposure. Currently, the efficacy of therapeutics is limited in malignant mesothelioma, and developing more effective therapies is the need of the hour. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), have attracted attention as therapeutic targets. To explore potential therapeutic targets, we focused on miR-142-3p expression, which was found to be significantly downregulated in mesothelioma cell lines in our previous study. Methods: Mesothelioma cell lines and tissues were validated for expression of miR-142-3p or integrin subunit alpha-V (ITGAV). We transfected mesothelioma cell lines with miR-142-3p mimic and ITGAV siRNA and analyzed their biological functions. Results: We found that miR-142-3p was significantly downregulated in mesothelioma tissues. Transfection with miR-142-3p mimic significantly suppressed cell proliferation, migration, and invasion. Bioinformatics analysis of potential targets of miR-142-3p identified ITGAV. Membrane ITGAV expression in mesothelioma cell lines was confirmed using immunocytochemistry. ITGAV was significantly upregulated in mesothelioma tissues. Moreover, transfection of miR-142-3p mimics into mesothelioma cell lines significantly suppressed ITGAV expression, indicating that miR-142-3p targets ITGAV. Next, ITGAV siRNA transfection into mesothelioma cell lines inhibited cell proliferation, migration, and invasion. Further investigation of cell adhesion mechanisms showed that the miR-142-3p/ITGAV axis specifically affects mesothelioma cell adhesion via vitronectin in the extracellular matrix. Conclusion: This study proposed that the miR-142-3p/ITGAV axis is involved in tumor progression in malignant mesothelioma.

Meta-analysis of expression and the targeting of cell adhesion associated genes in nine cancer types – A one research lab re-evaluation

Cancer presents as a highly heterogeneous disease with partly overlapping and partly distinct (epi)genetic characteristics. These characteristics determine inherent and acquired resistance, which need to be overcome for improving patient survival. In line with the global efforts in identifying druggable resistance factors, extensive preclinical research of the Cordes lab and others designated the cancer adhesome as a critical and general therapy resistance mechanism with multiple druggable cancer targets. In our study, we addressed pancancer cell adhesion mechanisms by connecting the preclinical datasets generated in the Cordes lab with publicly available transcriptomic and patient survival data. We identified similarly changed differentially expressed genes (scDEGs) in nine cancers and their corresponding cell models relative to normal tissues. Those scDEGs interconnected with 212 molecular targets from Cordes lab datasets generated during two decades of research on adhesome and radiobiology. Intriguingly, integrative analysis of adhesion associated scDEGs, TCGA patient survival and protein-protein network reconstruction revealed a set of overexpressed genes adversely affecting overall cancer patient survival and specifically the survival in radiotherapy-treated cohorts. This pancancer gene set includes key integrins (e.g. ITGA6, ITGB1, ITGB4) and their interconnectors (e.g. SPP1, TGFBI), affirming their critical role in the cancer adhesion resistome. In summary, this meta-analysis demonstrates the importance of the adhesome in general, and integrins together with their interconnectors in particular, as potentially conserved determinants and therapeutic targets in cancer.

Cell Response in Free-Packed Granular Systems.

The study of the interactions of living adherent cells with mechanically stable (visco)elastic materials enables understanding and exploitation of physiological phenomena mediated by cell-extracellular communication. Insights into the interaction of cells and surrounding objects with different stability patterns upon cell contact might unveil biological responses to engineer innovative applications. Here, we hypothesize that the efficiency of cell attachment, spreading, and movement across a free-packed granular bed of microparticles depends on the microparticle diameter, raising the possibility of a necessary minimum traction force for the reinforcement of cell-particle bonds and long-term cell adhesion. The results suggest that microparticles with diameters of 14-20 μm are prone to cell-mediated mobility, holding the potential of inducing early cell detachment, while objects with diameters from 38 to 85 μm enable long-lasting cell adhesion and proliferation. An in silico hybrid particle-based model that addresses the time-dependent biological mechanisms of cell adhesion is proposed, providing inspiration for engineering platforms to address healthcare-related challenges.