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Fibroblast-specific reduction of heparan sulfate suppresses pancreatic cancer growth in mice

ABSTRACT: we examined how HS-reduced fibroblasts are involved in the proliferation of pancreatic cancer by using mice in which Ext-1 expression is specifically suppressed in fibroblasts.

ORGANISM(S): Mus musculus Mus

PROVIDER: GSE203598 | GEO | 2022/06/13

REPOSITORIES: GEO

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Fibroblast-specific reduction of heparan sulfate suppresses colon tumor growth in mice

Project description:we examined how HS-reduced fibroblasts are involved in the proliferation of colon cancer by using mice in which Ext-1 expression is specifically suppressed in fibroblasts.

2022-06-13 | GSE203597 | GEO

Endothelial cell-specific reduction of heparan sulfate suppresses glioma growth in mice

Project description:we examined how HS-reduced vascular endothelial cells are involved in the proliferation of glioma by using mice in which Ext-1 expression is specifically suppressed in vascular endothelial cells.

2021-11-17 | GSE175419 | GEO

Fibroblast-specific reduction of heparan sulfate suppresses colon tumor growth and pancreatic cancer growth in mice

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-06-13 | GSE203602 | GEO

Fibroblast-specific reduction of heparan sulfate suppresses pancreatic cancer growth in mice

Project description:Fibroblast-specific reduction of heparan sulfate suppresses pancreatic cancer growth in mice

| PRJNA841564 | ENA

Endothelial cell-specific reduction of heparan sulfate suppresses glioma growth in mice.

Project description:PurposeHeparan sulfate (HS) is one of the factors that has been suggested to be associated with angiogenesis and invasion of glioblastoma (GBM), an aggressive and fast-growing brain tumor. However, it remains unclear how HS of endothelial cells is involved in angiogenesis in glioblastoma and its prognosis. Thus, we investigated the effect of endothelial cell HS on GBM development.MethodsWe generated endothelial cell-specific knockout of Ext1, a gene encoding a glycosyltransferase and essential for HS synthesis, and murine GL261 glioblastoma cells were orthotopically transplanted. Two weeks after transplantation, we examined the tumor progression and underlying mechanisms.ResultsThe endothelial cell-specific Ext1 knockout (Ext1 CKO ) mice exhibited reduced HS expression specifically in the vascular endothelium of the brain capillaries compared with the control wild-type (WT) mice. GBM growth was significantly suppressed in Ext1 CKO mice compared with that in WT mice. After GBM transplantation, the survival rate was significantly higher in Ext1 CKO mice than in WT mice. We investigated how the effect of fibroblast growth factor 2 (FGF2), which is known as an angiogenesis-promoting factor, differs between Ext1 CKO and WT mice by using an in vivo Matrigel assay and demonstrated that endothelial cell-specific HS reduction attenuated the effect of FGF2 on angiogenesis.ConclusionsHS reduction in the vascular endothelium of the brain suppressed GBM growth and neovascularization in mice.Supplementary informationThe online version contains supplementary material available at 10.1007/s12672-021-00444-3.

| S-EPMC8585801 | biostudies-literature

TFCP2 is a transcriptional regulator of heparan sulfate assembly and melanoma cell growth

Project description:Heparan sulfate (HS) is a long, linear polysaccharide that is ubiquitously expressed in all animal cells and plays a key role in many cellular processes, including cell signaling and development. Dysregulation of HS assembly has been implicated in pathophysiological conditions, such as tumorigenesis and rare genetic disorders. HS biosynthesis occurs in a non-template driven manner in the endoplasmic reticulum and Golgi through the activity a large group of biosynthetic enzymes. While much is known about its biosynthesis, little is understood about the regulation of HS assembly across diverse tissue types and disease states. To address this gap in knowledge, we recently performed genome-wide CRISPR/Cas9 screens to identify novel regulatory factors of HS biosynthesis. From these screens, we identified the alpha globin transcription factor, TFCP2, as a top hit. To investigate the role of TFCP2 in HS assembly, we targeted TFCP2 expression in human melanoma cells using the CRISPR/Cas9 system. TFCP2 knockout cells exhibited decreased fibroblast growth factor binding to cell surface HS, alterations in HS composition, and slowed cell growth compared to wildtype cells. Additionally, RNA sequencing revealed that TFCP2 regulates expression of multiple enzymes involved in HS assembly, including the secreted endosulfatase, SULF1. Pharmacological targeting of TFCP2 activity similarly reduced growth factor binding and increased SULF1 expression, and knockdown of SULF1 expression in TFCP2 mutant cells restored melanoma cell growth. Overall, these studies identify TFCP2 as a novel transcriptional regulator of HS and highlight HS-protein interactions as a possible target to slow melanoma growth.

2023-05-01 | GSE224599 | GEO

Fibroblast-specific reduction of heparan sulfate suppresses colon tumor growth in mice

Project description:Fibroblast-specific reduction of heparan sulfate suppresses colon tumor growth in mice

| PRJNA841566 | ENA

Effect of heparan sulfate cleavage on homeostatic gene expression in microvascular endothelial cells

Project description:Heparan sulfate (HS) in the vascular endothelial glycocalyx (eGC) is a critical regulator of blood vessel homeostasis. Trauma results in HS shedding from the eGC, but the impact of HS shedding on mechanisms of vascular injury and repair has not been evaluated. The objective of this work was to characterize the effect of eGC HS shedding on the transcriptional landscape of vascular endothelial cells. In vitro work was performed using flow conditioned primary human lung microvascular ECs treated with vehicle or heparin lyase III to simulate human heparanase activity. Bulk RNA sequencing was performed to determine differentially expressed gene-enriched pathways following heparin lyase III treatment. Pathway analysis demonstrated downregulation of genes that support cell junction integrity, EC polarity, and EC senescence while upregulating genes that promote cell differentiation and proliferation following HS shedding.

2024-08-14 | GSE260628 | GEO

Heparan sulfate regulates the fate decisions of human pluripotent stem cells

Project description:Heparan sulfate (HS) is an anionic polysaccharide generated by all animal cells. Studies in model organisms have revealed some of its critical developmental roles, though HS role in human pluripotent stem cell (hPSC) self-renewal and differentiation is poorly understood. We, therefore, generated HS-deficient hPSCs by disrupting EXT1 glycosyltransferase. The depletion of heparan sulfate resulted in impaired differentiation of EXT1-/- cells to the mesendoderm lineage. To elucidate the underlying mechanisms behind defective ME differentiation, we further assessed the global transcriptomic profiles of wildtype (WT) and EXT1-/- hPSCs following directed differentiation. The hierarchical gene clustering showed that the upregulated genes were mainly associated with neuronal development, whereas the downregulated genes were associated with extracellular matrix organization and regulation of signal transduction. Consistent with these findings, EXT1-/- hPSCs failed to activate FGF and Nodal pathways during mesendoderm induction. These results underscore the previously unexplored roles of heparan sulfate in the Activin/Nodal pathway. Taken together, our study provides insight into the mechanistic roles of HS in hPSC fate decisions.

2024-10-19 | GSE272332 | GEO

Specific 3-O-sulfated heparan sulfate domains regulate salivary gland basement membrane metabolism and epithelial differentiation [female]

Project description:FGF signaling is essential for salivary gland (SG) development and heparan sulfate (HS) regulation of FGFR function is determined by immense structural diversity of sulfated HS domains. The basement membrane (BM), containing HS proteoglycans, collagens and laminins, separates epithelia from stroma and controls growth factor-matrix cross-talk. 3-O-sulfotransferases generate highly 3-O-sulfated HS domains (3-O-HS) and Hs3st3a1 and Hs3st3b1 are enriched in myoepithelial cells (MECs), which produce BM and are a growth factor signaling hub. To investigate 3-O-HS regulation of MEC function and growth factor signaling, we generated Hs3st3a1;Hs3st3b1 double knockout (DKO) mice. The DKO HS loses specific highly 3-O-sulfated tetrasaccharides, which increases FGF/FGFR-complex binding to HS. During development this leads to increased FGFR-, BM- and MEC-related gene expression. However, in adult DKO SGs the secretory units containing acinar and MECs, have reduced MECs, increased BM and disrupted acinar polarity, resulting in salivary hypofunction. We used defined 3-O-sulfated-HS in FGFR pulldown assays and primary organ cultures to investigate 3-O-HS-dependent mechanisms regulating MEC development. We find that 3-O-HS modulates FGFR signaling to regulate MEC BM synthesis which is critical for secretory unit homeostasis and acinar function. Understanding how sulfated HS regulates development will inform the use of HS mimetics in organ regeneration.

2024-08-02 | GSE235185 | GEO

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