Hernandezbalslev6648

Pattern recognition receptors (PRRs) are germline-encoded host sensors of the innate immune system. Some human cancer cells have been reported to express PRRs. However, nucleic acid sensors in human cancers have not been studied in detail. Therefore, we systematically analyzed the expression, molecular cascade, and functions of TLR3, RIG-I, MDA5, LGP2, cGAS, and STING in human cancer cells. TLR3, TRIF, RIG-I, MDA5, LGP2, and MAVS were expressed in 22 cell lines. The majority of cell lines responded to only RIG-I ligands 5'-ppp-dsRNA, Poly(IC)-HMW, Poly(IC)-LMW, and/or Poly(dAdT), as revealed by IRF3 phosphorylation and IFN-β secretion. IFN-β secretion was inhibited by RIG-I and MAVS knockdown. cGAS and STING were co-expressed in 10 of 22 cell lines, but IFN-β secretion was not induced by STING ligands ISD, HSV60, VACV70, Poly(dGdC), and 3'3'-cGAMP in cGAS and STING intact cell lines. Further experiments revealed that the cGAS-STING pathway was activated, as revealed by TBK1 and IRF3 phosphorylation and IFN-β and ISG mRNA expression. These results suggest that human epithelial cancer cells respond to cytosolic RNA through the RIG-I-MAVS pathway but only sense cytosolic DNA through the cGAS-STING pathway. These findings are relevant for cancer immunotherapy approaches based on targeting nucleic acid receptors.Castration-resistant prostate cancer (CRPC) is the major cause of death from prostate cancer. Biomarkers to improve early detection and prediction of CRPC especially using non-invasive liquid biopsies could improve outcomes. Therefore, we investigated the plasma exosomal miRNAs associated with CRPC and their potential for development into non-invasive early detection biomarkers for resistance to treatment. RNA-sequencing, which generated approximately five million reads per patient, was performed to identify differentially expressed plasma exosomal miRNAs in 24 treatment-naive prostate cancer and 24 CRPC patients. RT-qPCR was used to confirm the differential expressions of six exosomal miRNAs, miR-423-3p, miR-320a, miR-99a-5p, miR-320d, miR-320b, and miR-150-5p (p = 7.3 × 10-8, 0.0020, 0.018, 0.0028, 0.0013, and 0.0058, respectively) firstly in a validation cohort of 108 treatment-naive prostate cancer and 42 CRPC patients. The most significant differentially expressed miRNA, miR-423-3p, was shown to be associated with CRPC with area under the ROC curve (AUC) = 0.784. Combining miR-423-3p with prostate-specific antigen (PSA) enhanced the prediction of CRPC (AUC = 0.908). A separate research center validation with 30 treatment-naive and 30 CRPC patients also confirmed the differential expression of miR-423-3p (p = 0.016). Finally, plasma exosomal miR-423-3p expression in CRPC patients was compared to 36 non-CRPC patients under androgen depletion therapy, which showed significantly higher expression in CRPC than treated non-CRPC patients (p less then 0.0001) with AUC = 0.879 to predict CRPC with no difference between treatment-naive and treated non-CRPC patients. Therefore, our findings demonstrate that a number of plasma exosomal miRNAs are associated with CRPC and miR-423-3p may serve as a biomarker for early detection/prediction of castration-resistance.Notch and Wnt signaling are highly conserved intercellular communication pathways involved in developmental processes, such as hematopoiesis. Even though data from literature support a role for these two pathways in both physiological hematopoiesis and leukemia, there are still many controversies concerning the nature of their contribution. Early studies, strengthened by findings from T-cell acute lymphoblastic leukemia (T-ALL), have focused their investigation on the mutations in genes encoding for components of the pathways, with limited results except for B-cell chronic lymphocytic leukemia (CLL); in because in other leukemia the two pathways could be hyper-expressed without genetic abnormalities. As normal and malignant hematopoiesis require close and complex interactions between hematopoietic cells and specialized bone marrow (BM) niche cells, recent studies have focused on the role of Notch and Wnt signaling in the context of normal crosstalk between hematopoietic/leukemia cells and stromal components. Amongst the latter, mesenchymal stromal/stem cells (MSCs) play a pivotal role as multipotent non-hematopoietic cells capable of giving rise to most of the BM niche stromal cells, including fibroblasts, adipocytes, and osteocytes. Indeed, MSCs express and secrete a broad pattern of bioactive molecules, including Notch and Wnt molecules, that support all the phases of the hematopoiesis, including self-renewal, proliferation and differentiation. Herein, we provide an overview on recent advances on the contribution of MSC-derived Notch and Wnt signaling to hematopoiesis and leukemia development.Increasing evidence suggests a strong interplay between autophagy and genomic stability. Recently, several papers have demonstrated a molecular connection between the DNA Damage Response (DDR) and autophagy and have explored how this link influences cell fate and the choice between apoptosis and senescence in response to different stimuli. The aberrant deregulation of this interplay is linked to the development of pathologies, including cancer and neurodegeneration. Ataxia-telangiectasia mutated kinase (ATM) is the product of a gene that is lost in Ataxia-Telangiectasia (A-T), a rare genetic disorder characterized by ataxia and cerebellar neurodegeneration, defects in the immune response, higher incidence of lymphoma development, and premature aging. Importantly, ATM kinase plays a central role in the DDR, and it can finely tune the balance between senescence and apoptosis activated ATM promotes autophagy and in particular sustains the lysosomal-mitochondrial axis, which in turn promotes senescence and inhibits apoptosis. Therefore, ATM is the key factor that enables cells to escape apoptosis by entering senescence through modulation of autophagy. Importantly, unlike apoptotic cells, senescent cells are viable and have the ability to secrete proinflammatory and mitogenic factors, thus influencing the cellular environment. In this review we aim to summarize recent advances in the understanding of molecular mechanisms linking DDR and autophagy to senescence, pointing out the role of ATM kinase in these cellular responses. The significance of this regulation in the pathogenesis of Ataxia-Telangiectasia will be discussed.To coordinate specialized organs, inter-tissue communication appeared during evolution. Consequently, individual organs communicate their states via a vast interorgan communication network (ICN) made up of peptides, proteins, and metabolites that act between organs to coordinate cellular processes under homeostasis and stress. However, the nature of the interorgan signaling could be even more complex and involve mobilization mechanisms of unconventional cells that are still poorly described. Mesenchymal stem/stromal cells (MSCs) virtually reside in all tissues, though the biggest reservoir discovered so far is adipose tissue where they are named adipose stromal cells (ASCs). MSCs are thought to participate in tissue maintenance and repair since the administration of exogenous MSCs is well known to exert beneficial effects under several pathological conditions. However, the role of endogenous MSCs is barely understood. Though largely debated, the presence of circulating endogenous MSCs has been reported in multiple pathophysiological conditions, but the significance of such cell circulation is not known and therapeutically untapped. In this review, we discuss current knowledge on the circulation of native MSCs, and we highlight recent findings describing MSCs as putative key components of the ICN.Substantial number of breast cancer (BC) patients undergoing radiation therapy (RT) develop local recurrence over time. During RT therapy, cells can gradually acquire resistance implying adaptive radioresistance. Here we probe the mechanisms underlying this acquired resistance by first establishing radioresistant lines using ZR-75-1 and MCF-7 BC cells through repeated exposure to sub-lethal fractionated dose of 2Gy up to 15 fractions. Radioresistance was found to be associated with increased cancer stem cells (CSCs), and elevated EpCAM expression in the cell population. A retrospective analysis of TCGA dataset indicated positive correlation of high EpCAM expression with poor response to RT. Intriguingly, elevated EpCAM expression in the radioresistant CSCs raise the bigger question of how this biomarker expression contributes during radiation treatment in BC. Thereafter, we establish EpCAM overexpressing ZR-75-1 cells (ZR-75-1EpCAM), which conferred radioresistance, increased stemness through enhanced AKT activation and induced a hybrid epithelial/mesenchymal phenotype with enhanced contractility and invasiveness. In line with these observations, orthotopic implantation of ZR-75-1EpCAM cells exhibited faster growth, lesser sensitivity to radiation therapy and increased lung metastasis than baseline ZR-75-1 cells in mice. In summary, this study shows that similar to radioresistant BC cells, EpCAM overexpressing cells show high degree of plasticity and heterogeneity which ultimately induces radioresistant and metastatic behavior of cancer cells, thus aggravating the disease condition.Extracellular vesicles, phospholipid bilayer-membrane vesicles of cellular origin, are emerging as nanocarriers of biological information between cells. Extracellular vesicles transport virtually all biologically active macromolecules (e.g., nucleotides, lipids, and proteins), thus eliciting phenotypic changes in recipient cells. However, we only partially understand the cellular mechanisms driving the encounter of a soluble ligand transported in the lumen of extracellular vesicles with its cytosolic receptor a step required to evoke a biologically relevant response. In this context, we review herein current evidence supporting the role of two well-described cellular transport pathways the endocytic pathway as the main entry route for extracellular vesicles and the autophagic pathway driving lysosomal degradation of cytosolic proteins. The interplay between these pathways may result in the target engagement between an extracellular vesicle cargo protein and its cytosolic target within the acidic compartments of the cell. This mechanism of cell-to-cell communication may well own possible implications in the pathogenesis of neurodegenerative disorders.Cellular phenotypes on bioactive compound treatment are a result of the downstream targets of the respective treatment. Here, a computational approach is taken for downstream subcellular target identification to understand the basis of the cellular response. This response is a readout of cellular phenotypes captured from cell-painting-based light microscopy images. NSC697923 cost The readouts are morphological profiles measured simultaneously from multiple cellular organelles. Cellular profiles generated from roughly 270 diverse treatments on bone cancer cell line form the high content screen used in this study. Phenotypic diversity across these treatments is demonstrated, depending on the image-based phenotypic profiles. Furthermore, the impact of the treatments on specific organelles and associated organelle sensitivities are determined. This revealed that endoplasmic reticulum has a higher likelihood of being targeted. Employing multivariate regression overall cellular response is predicted based on fewer organelle responses.