Chemical, molecular, and single cell analysis reveal chondroitin sulfate proteoglycan aberrancy in fibrolamellar carcinoma
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ABSTRACT:
PROVIDER: PRJNA835448 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19097905.fastq.gz | Fastqsanger.gz | |||
| SRR19097905_1.fastq.gz | Fastqsanger.gz | |||
| SRR19097905_2.fastq.gz | Fastqsanger.gz | |||
| SRR19097906.fastq.gz | Fastqsanger.gz | |||
| SRR19097906_1.fastq.gz | Fastqsanger.gz |
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Project description:Fibrolamellar carcinoma (FLC) is an aggressive liver cancer that predominantly afflicts adolescents and young adults. Patients with FLC are characterized by a heterozygous deletion on chromosome 19 that creates an oncogenic gene fusion, DNAJB1-PRKACA. The extracellular environment of FLC tumors is poorly characterized and may contribute to cancer progression, metastasis, and/or drug resistance. To bridge this knowledge gap, we propose to assess pathways relevant to proteoglycans, a major component of the extracellular matrix. We leveraged single-cell ATAC-seq to analyze the diversity of VCAN accessibility across different cell types.
2022-05-20 | GSE202315 | GEO
Project description:Fibrolamellar carcinoma (FLC) is an aggressive liver cancer with no effective therapeutic options. The extracellular environment of FLC tumors is poorly characterized and may contribute to cancer growth and/or metastasis. To bridge this knowledge gap, we assessed pathways relevant to proteoglycans, a major component of the extracellular matrix. We first analyzed gene expression data from FLC and nonmalignant liver tissue (n = 27) to identify changes in glycosaminoglycan (GAG) biosynthesis pathways and found that genes associated with production of chondroitin sulfate, but not other GAGs, are significantly increased by 8-fold. We then implemented a novel LC/MS-MS based method to quantify the abundance of different types of GAGs in patient tumors (n = 16) and found that chondroitin sulfate is significantly more abundant in FLC tumors by 6-fold. Upon further analysis of GAG-associated proteins, we found that versican (VCAN) expression is significantly upregulated at the mRNA and protein levels, the latter of which was validated by IHC. Finally, we performed single-cell assay for transposase-accessible chromatin sequencing on FLC tumors (n = 3), which revealed for the first time the different cell types in FLC tumors and also showed that VCAN is likely produced not only from FLC tumor epithelial cells but also activated stellate cells. Our results reveal a pathologic aberrancy in chondroitin (but not heparan) sulfate proteoglycans in FLC and highlight a potential role for activated stellate cells.SignificanceThis study leverages a multi-disciplinary approach, including state-of-the-art chemical analyses and cutting-edge single-cell genomic technologies, to identify for the first time a marked chondroitin sulfate aberrancy in FLC that could open novel therapeutic avenues in the future.
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Project description:Analysis of Cellular Resistance to Clostridioides difficile TcdB2 Reveals Regulators of Chondroitin Sulfate Proteoglycan 4
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Project description:Here, using LC-MS/MS, we describe for the first time a linkage region trisaccharide comprising [-GlcUA-Gal-Xyl-O-] as an alternative point of entry for glycosaminoglycan (GAG) biosynthesis. The trisaccharide was identified in the proteoglycan bikunin from urine of human healthy donors present as a disulfated pentasaccharide, [deltaHexUA-GalNAc(S)-GlcUA-Gal(S)-Xyl-O-] after chondroitinase ABC degradation. Furthermore, it was identified in chondroitin sulfate primed on xylosides isolated from human cell lines, present as the corresponding disulfated pentasaccharide after chondroitinase ABC degradation.
2019-02-25 | PXD011855 | Pride
Project description:The critical role of chondroitin sulfate proteoglycan interactions with receptor PTPσ in the inhibition of neural repair after stroke
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Project description:Chondroitin sulfate proteoglycans are integral components of the extracellular matrix. These are composed of repeating disaccharide units of glucuronic acid and N-acetylgalactosamine linked to a serine residue on the core protein through an oligosaccharide linker. The functions of chondroitin sulfate proteoglycans are regulated by the disaccharide heteropolymers attached to the core protein. The degree of sulfation and modifications on the oligosaccharide linker differs in different tissues depending upon its function. Here, we characterized the chondroitin sulfate-linked peptides using mass spectrometric-based glycoproteomics approach. We analyzed plasma, urine and fibroblasts from apparently healthy individuals by mass spectrometry. We identified 230 glycopeptides belonging to 25 chondroitin sulfate-linked proteoglycans.
2022-10-13 | PXD029400 | Pride
Project description:Proteoglycans, a class of carbohydrate-modified proteins, often modulate growth factor signaling on the cell surface. However, the molecular mechanism by which proteoglycans regulate signal transduction is largely unknown. In this study, using a recently developed glycoproteomic method, we found that Windpipe (Wdp) is a novel chondroitin sulfate proteoglycan (CSPG) in Drosophila. Wdp is a single-pass transmembrane protein with leucin-rich repeat (LRR) motifs and bears three CS sugar chain attachment sites in the extracellular domain. Here we show that Wdp modulates the Hedgehog (Hh) pathway. In the wing disc, overexpression of wdp inhibits Hh signaling, which is dependent on its CS chains and the LRR motifs. The wdp null mutant flies show a specific defect (supernumerary scutellar bristles) known to be caused by Hh overexpression. RNA interference knockdown and mutant clone analyses showed that loss of wdp leads to the up-regulation of Hh signaling. Altogether, our study demonstrates a novel role of CSPGs in regulating Hh signaling.
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Project description:Proteoglycans and their constituent glycosaminoglycan (GAG) have been proposed to be involved in the inhibition of mineralization in unmineralized tissue, predentin. Among the proteoglycans secreted by odontoblasts, we focused on the large chondroitin sulfate proteoglycan, versican, for its large binding capacity for calcium ions. The aims of this study were the determination of the full-length sequence and splicing variants of the porcine versican, and the detection of versican in the porcine predentin. The complete coding sequence of the porcine versican mRNA was cloned to be 11,775 nucleotides long and encode 3,924 amino acids, and four splicing variants, V0, V1, V2 and V3, were characterized in the isolated porcine cartilage cells. The number of potential GAG attachment sites was 15 in the V0 variant, 13 in the V1 variant, 2 in the V2 variant and 0 in the V3 variant. They were deposited in DDBJ. The V1 variant was determined by RT-PCR in the odontoblasts, dental papilla cells, dental follicle cells, periodontal ligament cells, dental pulp cells, and gingival cells of pigs, although a small amount of the V0 valiant was found in the dental papilla cells. The predentin was prepared from developing porcine permanent incisor tooth germs and its soluble proteins were extracted in order to be partially characterized by protein and proteinase profiles. The versican V1 cleavage products were detected in the predentin extract by Western blotting analysis. These results suggested that the versican splice variant V1 implicates both the control of the mineralization and the activities of the predentin metalloproteinases, because it has 13 GAG chains that bind a large amount of calcium.
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Project description:Disruptions in neuronal dendrite development alter brain circuitry and are associated with debilitating neurological disorders. Nascent apical dendrites of cortical excitatory neurons project into the marginal zone (MZ), a cell-sparse layer characterized by intense chondroitin sulfate proteoglycan (CSPG) expression. Paradoxically, CSPGs are known to broadly inhibit neurite growth and regeneration. This raises the possibility that the growing apical dendrite is somehow insensitive to CSPG-mediated neurite growth inhibition. To test this, developing cortical neurons were challenged with both soluble CSPGs and CSPG-positive stripe substrates in vitro Soluble CSPGs inhibited dendritic growth and cortical dendrites respected CSPG stripe boundaries, effects that could be counteracted by prior CSPG inactivation by chondroitinase. Importantly, addition of Reelin, an extracellular signaling protein highly expressed in the MZ, partially rescued dendritic growth in the presence of CSPGs. High-resolution confocal imaging revealed that the CSPG-enriched areas of the MZ spatially correspond with the areas of reduced dendritic density in the Reelin null (reeler) cortex compared with controls. Chondroitinase injections into reeler explants resulted in increased dendritic growth into the MZ, recovering to near wild-type levels. Activation of the serine threonine kinase Akt is required for Reelin-dependent dendritic growth and we find that CSPGs induce Akt dephosphorylation, an effect that can be counteracted by Reelin addition. In contrast, CSPG application had no effect on the cytoplasmic adaptor Dab1, which is rapidly phosphorylated in response to Reelin and is upstream of Akt. These findings suggest CSPGs do inhibit cortical dendritic growth, but this effect can be counteracted by Reelin signaling.
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Project description:Chondroitin sulfate proteoglycans (CSPGs), which are enriched in demyelinating plaques in neurodegenerative diseases, such as multiple sclerosis (MS), impair remyelination by inhibiting the migration and differentiation of oligodendrocyte precursor cells (OPCs) in the central nervous system (CNS). We herein show that protamine (PRM, also known as a heparin antagonist) effectively neutralizes the inhibitory activities of CSPGs, thereby enhancing OPC differentiation and (re)myelination in mice. Cell-based assays using mouse OPC-like OL1 cells revealed that the PRM treatment exerted masking effects on extracellular CSPGs and improved oligodendrocyte differentiation on inhibitory CSPG-coated substrates. PRM also bound to the extracellular region of protein tyrosine phosphatase receptor type Z (PTPRZ), a membrane-spanning CSPG predominantly expressed in OPCs, and functioned as a ligand mimetic of PTPRZ, thereby suppressing its negative regulatory activity on oligodendrocyte differentiation. In primary cultures, the differentiation of OPCs from wild-type and Ptprz-deficient mice was equally enhanced by PRM. Moreover, the intranasal administration of PRM accelerated myelination in the developing mouse brain, and its intracerebroventricular administration stimulated remyelination after cuprizone-induced demyelination. These results indicate that PRM has CSPG-neutralizing activity which promotes oligodendrocyte differentiation under developmental and morbid conditions.
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