Spatial regulation of the glycocalyx component Podocalyxin is a switch for pro-metastatic function
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ABSTRACT:
PROVIDER: PRJEB53371 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR9827790_1.fastq.gz | Fastqsanger.gz | |||
| ERR9827790_2.fastq.gz | Fastqsanger.gz | |||
| ERR9827791_1.fastq.gz | Fastqsanger.gz | |||
| ERR9827791_2.fastq.gz | Fastqsanger.gz | |||
| ERR9827792_1.fastq.gz | Fastqsanger.gz |
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Project description:The sialomucin Podocalyxin (PODXL) is required for normal tissue development and apicobasal cell polarity by promoting lumen formation. Strikingly, high PODXL expression is also associated with metastasis and poor clinical outcome in multiple tumour types, such as prostate cancer. Utilising prostate cancer cell lines that have the highest RNA levels of PODXL (PC3), we identified subpopulations that do not differ drastically in their overall expression of PODXL but have the stable feature of either high or low surface localisation of PODXL. High surface PODXL promote robust invasion of cells into extracellular matrix. Notably, knockdown of PODXL gave the same effect - reduced invasion - as having PODXL expressed but not being localised to the surface. We performed transcriptional profiling via RNA-sequencing of PC3 cells (PC3 parental, PC3 High surface PODXL and PC3 Low surface PODXL) to uncover possible regulators of PODXL surface expression.
2023-03-17 | E-MTAB-11793 | biostudies-arrayexpress
Project description:The sialomucin Podocalyxin (PODXL) is required for normal tissue development and apicobasal cell polarity by promoting lumen formation. Remarkably, high PODXL expression is also associated with metastasis and poor clinical outcome in multiple tumour types, such as prostate cancer. We performed extensive in vitro analysis of prostate cancer cell lines that have the highest RNA levels of PODXL (PC3). We identified that elevated PODXL promoted invasion. We also isolated subpopulations that do not differ drastically in their overall expression of PODXL but have the stable feature of either high or low surface localisation of PODXL. High surface PODXL promote robust invasion of cells into extracellular matrix. Notably, knockdown of PODXL gave the same effect - reduced invasion - as having PODXL expressed but not being localised to the surface.By using proteomic analysis, we aimed to identify the strongest interactors of PODXL, trying to uncover molecular mechanisms that control PODXL function and localization.
2023-03-11 | PXD032911 | Pride
Project description:The glycocalyx component and sialomucin podocalyxin (PODXL) is required for normal tissue development by promoting apical membranes to form between cells, triggering lumen formation. Elevated PODXL expression is also associated with metastasis and poor clinical outcome in multiple tumor types. How PODXL presents this duality in effect remains unknown. We identify an unexpected function of PODXL as a decoy receptor for galectin-3 (GAL3), whereby the PODXL-GAL3 interaction releases GAL3 repression of integrin-based invasion. Differential cortical targeting of PODXL, regulated by ubiquitination, is the molecular mechanism controlling alternate fates. Both PODXL high and low surface levels occur in parallel subpopulations within cancer cells. Orthotopic intraprostatic xenograft of PODXL-manipulated cells or those with different surface levels of PODXL define that this axis controls metastasis in vivo. Clinically, interplay between PODXL-GAL3 stratifies prostate cancer patients with poor outcome. Our studies define the molecular mechanisms and context in which PODXL promotes invasion and metastasis.
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Project description:Loss of the Endothelial Glycocalyx Component EMCN Leads to Glomerular Impairment
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Project description:Endomucin (EMCN), an endothelial-specific glycocalyx component, was found to be highly expressed by the endothelium of the renal glomerulus. We reported an anti-inflammatory role of EMCN and its involvement in the regulation of vascular endothelial growth factor (VEGF) activity through modulating VEGF receptor 2 (VEGFR2) endocytosis. The goal of this study is to investigate the phenotypic and functional effects of EMCN deficiency using the first global EMCN knockout mouse model.Global EMCN knockout mice were generated by crossing EMCN-floxed mice with ROSA26-Cre mice. Flow cytometry was employed to analyze infiltrating myeloid cells in the kidneys. The ultrastructure of the glomerular filtration barrier was examined by transmission electron microscopy, while urinary albumin, creatinine, and total protein levels were analyzed from freshly collected urine samples. Expression and localization of EMCN, EGFP, CD45, CD31, CD34, podocin, albumin, and α-smooth muscle actin were examined by immunohistochemistry. Mice were weighed regularly and their systemic blood pressure was measured using a non-invasive tail-cuff system. Glomerular endothelial cells and podocytes were isolated by fluorescence-activated cell sorting for RNA sequencing. Transcriptional profiles were analyzed to identify differentially expressed genes in both endothelium and podocytes, followed by gene ontology analysis of up- and down-regulated genes. Protein levels of EMCN, albumin, and podocin were quantified by Western blot.EMCN-/- mice were viable with no gross anatomical defects in kidneys. The EMCN-/- mice exhibited increased infiltration of CD45+ cells, with an increased proportion of Ly6GhighLy6Chigh myeloid cells and higher VCAM-1 expression. EMCN-/- mice displayed albuminuria with increased albumin in the Bowman's space compared to the EMCN+/+ littermates. Glomeruli in EMCN-/- mice revealed fused and effaced podocyte foot processes and disorganized endothelial fenestrations. We found no significant difference in blood pressure between EMCN knockout mice and their wild-type littermates. RNA sequencing of glomerular endothelial cells revealed downregulation of cell-cell adhesion and MAPK/ERK pathways, along with glycocalyx and extracellular matrix remodeling. In podocytes, we observed reduced VEGF signaling and alterations in cytoskeletal organization. Notably, there was a significant decrease in both mRNA and protein levels of podocin, a key component of the slit diaphragm.
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Project description:Embryo implantation is a key step in establishing pregnancy and a major limiting factor in IVF. Implantation requires the endometrium, the inner lining of the uterus, to transform from a non-receptive to a receptive state, to allow embryos to attach to the surface and enter into the tissue. However, the fundamental mechanisms governing receptivity are not well understood. Here we show that transmembrane protein podocalyxin is a major and clinically significant factor regulating human endometrial receptivity. Podocalyxin is expressed in all endometrial epithelial cells in the non-receptive state but is selectively down-regulated in the luminal epithelium at receptivity. We present evidence that podocalyxin critically governs the barrier function of the endometrial epithelium, likely as an intrinsic protective mechanism, rendering it non-receptive to an embryo. In addition, podocalyxin suppresses genes promoting receptivity (eg LIF, CSF1) but stimulates those inhibiting implantation (eg WNT7A, LEFTY2). Down-regulation of podocalyxin in the luminal epithelium, likely mediated by progesterone, selectively converts the endometrial surface to a more adhesive state that facilitates embryo attachment and penetration. Furthermore, inadequate down-regulation of podocalyxin in the endometrial luminal epithelium is associated with poorer implantation rates in IVF. We thus propose that podocalyxin promotes the barrier function of human endometrial epithelial cells and critically regulates receptivity for embryo implantation.
2021-04-01 | GSE148274 | GEO
Project description:The glycocalyx consists of glycoproteins, glycolipids and extracellular polysaccharides at the cell surface which mediate viscoelastic and electrostatic barrier function. In molecular interactions the glycocalyx is thought to segregate locally to facilitate receptor-ligand binding, yet high-resolution maps of glycocalyx domains in cell-cell and cell-matrix interactions are lacking. We here applied TMTH-sulfoximine (THS)-based biorthogonal chemistry in live-cell culture and demonstrate much-enhanced glycocalyx detection, compared to established dibenzocyclooctyne-based labeling. Using superresolution microscopy, we identified micron-scale moderately diminished glycocalyx in cell-cell contacts and subtotal depletion in protrusions at the leading and trailing edges and membrane blebs when cells invaded 3D fibrillar matrix. At contacts to collagen fibrils, focal integrin clusters segregated in outward-protrusive nanodomains from glycocalyx (distance: 350 nm), forming adhesion sites of low glycocalyx content. Thus, THS-based next-generation bioorthogonal labelling of live cells identifies micro- and nanodomains with altered glycocalyx density, implicating local glycocalyx downregulation in functional cell-cell and cell-matrix interactions.
2025-03-18 | GSE287160 | GEO
Project description:The transmembrane signals maintain the pluripotency of human pluripotent stem cells (hPSCs) are rarely investigated. A transmembrane glycoprotein, podocalyxin-like protein 1 (PODXL, also called podocalyxin like protein-1, PCLP1, Gp200/GCTM-2, MEP21, and Thrombomucin), aside from its well-known role in tumor malignancy, very little is known about its functions in hPSCs. In order to map the early signals triggered by PODXL, after 3 days of PODXL overexpression, a comprehensive gene expression profile changes were analyzed by cDNA microarray.
2019-12-01 | GSE127218 | GEO
Project description:Multi-component epigenetic control of pro-invasive genes in cancer cells
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