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Extracellular matrix sulfation in the tumor microenvironment stimulates cancer stemness and invasiveness

ABSTRACT: Tumor extracellular matrices (ECM) exhibit aberrant changes in composition and mechanics compared to normal tissues. Proteoglycans (PG) are vital regulators of cellular signaling in the ECM with ability to modulate receptor tyrosine kinase (RTK) activation via their sulfated glycosaminoglycan (sGAG) side chains. However, their role on tumor cell behavior is controversial. Here, we demonstrate that PGs are heavily expressed in lung adenocarcinoma patients in correlation with invasive phenotype and poor prognosis. We developed an engineered human lung tumor model which recapitulate the increase of sGAGs in tumors in an organotypic matrix with independent control of stiffness, viscoelasticity, ligand density and porosity. Our model reveals that increased sulfation stimulates extensive proliferation, epithelial-mesenchymal transition and stemness in cancer cells. We identified the FAK-PI3K-Akt signaling axis as a mediator of sulfation-induced molecular changes in cells upon activation of a distinct set of RTKs within tumor-mimetic hydrogels. We employed an integrative omics and network modeling approach to uncover the transcriptomic landscape of tumor cells in response to sulfation which demonstrated resemblance to PG-rich patient tumors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE273281 | GEO | 2024/07/29

REPOSITORIES: GEO

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Heparan Sulfation Dependent FGF Signalling Maintains ES Cells Primed for Differentiation in a Heterogeneous State

Project description:Embryonic stem (ES) cells continuously decide whether to maintain pluripotency or differentiate. While exogenous LIF and BMP4 perpetuate a pluripotent state, less is known about factors initiating differentiation. We show that heparan sulfate (HS) proteoglycans are critical co-receptors for signals inducing ES cell differentiation. Genetic targeting of NDST1 and 2, two enzymes required for N-sulfation of proteoglycans, blocked differentiation. This phenotype was rescued by HS presented in trans or by soluble heparin. NaClO3-, which reduces sulfation of proteoglycans, potently blocked differentiation of wild type cells. Mechanistically, N-sulfation was identified to be critical for functional autocrine FGF4 signalling. Micro array analysis identified the pluripotency maintaining transcription factors Nanog, KLF2/4/8, Tbx3 and Tcf3 to be negatively regulated, whereas markers of differentiation such as Gbx2, Dnmt3b, FGF5 and Brachyury were induced by sulfation-dependent-FGFR signalling. We show that several of these genes are heterogeneously expressed in ES cells and targeting of heparan sulfation or FGFR-signalling facilitated a homogenous Nanog/KLF4/Tbx3 positive ES cell state. This finding suggests that the recently discovered heterogeneous state of ES cells is regulated by HS-dependent FGFR signalling. Similarly, culturing blastocysts with NaClO3- eliminated GATA6 positive primitive endoderm progenitors generating a homogenous Nanog positive inner cell mass. Functionally, reduction of sulfation robustly improved de novo ES cell derivation efficiency. We conclude that N-sulfated HS is required for FGF4 signalling to maintain ES cells primed for differentiation in a heterogeneous state. Inhibiting this pathway facilitates a more naÃ¯ve ground state. Four groups with three biological replicates and a technical duplicate in each

2010-04-09 | E-GEOD-15974 | biostudies-arrayexpress

Installation of O-glycan sulfation capacities in human HEK293 cells

Project description:The human genome contains at least 35 genes that encode Golgi sulfotransferases functioning in the secretory pathway, where they are involved in decorating glycosaminoglycans, glycolipids, and glycoproteins with sulfate groups. Our insight into the sulfotransferases that serve glycoproteins and in particular GalNAc-type O-glycoproteins is limited, yet a number of important interactions with sulfated glycans by e.g. Selectins, Galectins, and Siglecs are thought to mainly rely on sulfated O-glycans. Moreover, sulfated mucins appear to be accumulated in respiratory diseases, arthritis and cancer. To explore further the genetic and biosynthetic regulation of sulfated O-glycans, we have started to expand a cell-based glycan array in the human HEK293 cell line with sulfation capacities. Here, we stably engineered O-glycan sulfation capacities in HEK293 cells by site-directed knock-in of sulfotransferase genes, in combination with knockout of endogenous core2 and/or sialylation capacities, to enable production of mucin reporters with sulfated O-glycans. Expression of GAL3ST2 in HEK293 cells resulted in sulfation of core1 and core2 O-glycans, whereas expression of GAL3ST4 resulted in sulfation of core1 only. We used the engineered cell library to dissect the binding specificity of galectin-4 and confirmed binding to the 3-O-sulfo-core1 O-glycan

2022-02-17 | PXD028982 | Pride

Heparan Sulfation Dependent FGF Signalling Maintains ES Cells Primed for Differentiation in a Heterogeneous State

2009-11-13 | GSE15974 | GEO

Semi-Synthesis of an Evasin from Tick Saliva Reveals a Critical Role of Tyrosine Sulfation for Chemokine Binding and Inhibition

Project description:Blood feeding arthropods produce anti-inflammatory salivary proteins called evasins that function through inhibition of chemokine-receptor signalling in the host. Herein, we show that the evasin ACA-01 from the Amblyomma cajennense tick can be post-translationally sulfated at two tyrosine residues, albeit as a mixture of sulfated variants. Homogenously sulfated variants of the proteins were efficiently assembled via a semi-synthetic native chemical ligation strategy. Sulfation significantly improved the binding affinity of ACA-01 for a range of pro-inflammatory chemokines and also enhanced the ability of ACA-01 to inhibit chemokine signalling through cognate receptors. Comparisons of evasin sequences and structural data suggest that tyrosine sulfation serves as a receptor mimetic strategy for recognizing and suppressing the pro-inflammatory activity of a wide variety of mammalian chemokines. As such, the use incorporation of this PTM or mimics thereof into evasins may provide a strategy to optimize these salivary tick proteins for anti-inflammatory applications

2020-05-15 | PXD016778 | Pride

Inhibition of the SLC35B2-TPST2 axis of tyrosine sulfation attenuates the growth and metastasis of pancreatic ductal adenocarcinoma

Project description:Background & Aims: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer deaths in the United States. Tyrosine sulfation, catalyzed by the tyrosylprotein sulfotransferase 2 (TPST2), is a post-translational modification essential for protein-protein interactions and cellular functions. SLC35B2 is a key transporter that transports the universal sulfate donor 3’-phosphoadenosine 5’-phosphosulfate (PAPS) into the Golgi apparatus where the protein sulfation occurs. The goal of this study is to determine whether and how SLC35B2-TPST2 axis of tyrosine sulfation plays a role in PDAC. Methods: Gene expression was analyzed in PDAC patients and mice. Human PDAC MIA PaCa-2 and PANC-1 cells were used for in vitro studies. TPST2 deficient MIA PaCa-2 cells were generated to assess xenograft tumor growth in vivo. Mouse PDAC cells derived from the KrasLSL-G12D/+;Tp53L/+;Pdx1-Cre (KPC) mice were used to generate Tpst2 KO KPC cells to evaluate tumor growth and metastasis in vivo. Results: High expressions of SLC35B2 and TPST2 were correlated with poor PDAC patient survival. Knockdown of SLC35B2 or TPST2, or pharmacological inhibition of sulfation inhibited PDAC cell proliferation and migration in vitro. TPST2 deficient MIA PaCa-2 cells exhibited inhibited xenograft tumor growth. Orthotopic inoculation of Tpst2 KO KPC cells in mice showed inhibition of primary tumor growth, local invasion, and metastasis. Mechanistically, the integrin ITGB4 was found to be a novel substrate of TPST2. Inhibition of sulfation destabilizes ITGB4 protein, which may have accounted for the suppression of metastasis. Conclusions: Targeting the SLC35B2-TPST2 axis of tyrosine sulfation may represent a novel approach for therapeutic intervention of PDAC.

2023-10-08 | GSE215104 | GEO

Extracellular Matrix Viscoelasticity Promotes Liver Cancer Progression in Pre-Cirrhotic NASH

Project description:Type 2 diabetes mellitus (T2DM) is a major risk factor for hepatocellular carcinoma (HCC). Changes in extracellular matrix (ECM) mechanics contribute to cancer development, and increased stiffness is known to promote HCC progression in cirrhotic conditions. T2DM is characterized by an accumulation of advanced glycation end products (AGEs) in the ECM; however, how this affects HCC in non-cirrhotic conditions is unclear. Here, we find that in patients and animal models AGEs promote changes in collagen architecture and enhance ECM viscoelasticity, with greater viscous dissipation and faster stress relaxation, but not changes in stiffness. High AGEs and viscoelasticity combined with oncogenic b-catenin signaling promote HCC induction, while inhibiting AGEs production, reconstituting the clearance receptor AGER1, or breaking AGE-mediated collagen crosslinks reduce viscoelasticity and HCC growth. Matrix analysis and computational modeling demonstrate that lower interconnectivity of AGEs-bundled collagen matrix, marked by shorter fiber length and greater heterogeneity, enhance viscoelasticity. Mechanistically, animal studies and 3D cell cultures show that enhanced viscoelasticity promotes HCC cell proliferation and invasion through an integrin β1–Tensin 1–YAP mechanotransduction pathway. These results reveal for the first time that AGEs-mediated structural changes enhance ECM viscoelasticity, and that viscoelasticity can drive cancer progression in vivo, independent of stiffness.

2023-10-14 | GSE245016 | GEO

Identification of human genes of which expression are induced by 4MU-xyloside treatment

Project description:The Golgi stress response is a homeostatic mechanism that augments the functional capacity of the Golgi apparatus when Golgi function becomes insufficient (Golgi stress). Three response pathways of the Golgi stress response have been identified in mammalian cells, the TFE3, HSP47 and CREB3 pathways, which augment the capacity of specific Golgi functions such as N-glycosylation, anti-apoptotic activity and pro-apoptotic activity, respectively. On the contrary, glycosylation of proteoglycans (PGs) is another important function of the Golgi, although the response pathway upregulating expression of glycosylation enzymes for PGs in response to Golgi stress remains unknown. Here, we found that expression of glycosylation enzymes for PGs was induced upon insufficiency of PG glycosylation capacity in the Golgi (PG-Golgi stress), and that transcriptional induction of genes encoding glycosylation enzymes for PGs was independent of the known Golgi stress response pathways and ER stress response. Promoter analyses of genes encoding these glycosylation enzymes revealed the novel enhancer element PGSE, which regulates their transcriptional induction upon PG-Golgi stress. From these observations, the response pathway we discovered is a novel Golgi stress response pathway, which we have named the PG pathway.

2018-08-01 | GSE117938 | GEO

Identification of human gene expression induced by 4MU-xyloside treatment

2018-09-14 | GSE119909 | GEO

Gut Microbiota Metabolite Indole-3-Acetic Acid Maintains Intestinal Epithelial Homeostasis Through Mucin Sulfation

Project description:The incidence and prevalence of inflammatory bowel disease (IBD) is gradually increasing. A high-fat diet (HFD) is known to disrupt intestinal homeostasis and aggravate IBD, yet the underlying mechanisms remain largely undefined. Here, a positive correlation between dietary fat intake and disease severity in both IBD patients and HFD-fed mice is observed. HFD induces a significant decrease in indole-3-acetic acid (IAA) and lead to intestinal barrier damage. Furthermore, IAA supplementation enhances the intestinal mucin sulfation and effectively alleviates colitis. Mechanistically, IAA upregulates key molecules involved in mucin sulfation, including Papss2 and Slc35b3, the synthesis enzyme and the transferase of 3'-phosphoadenosine-5'-phosphosulfate (PAPS), via the Aryl Hydrocarbon Receptor (AHR). More importantly, AHR can directly bind to the transcription start site of Papss2. Oral administration of Lactobacillus reuteri, which can produce IAA, contributes to protecting against colitis and promoting mucin sulfation, while the modified L. reuteri strain lacking the iaaM gene (LactobacillusΔiaaM) and the ability to produce IAA fails to exhibit such effects. Overall, IAA enhances intestinal mucin sulfation through AHR, contributing to the protection of intestinal homeostasis.

2024-05-26 | GSE249996 | GEO

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Project description:Plants possess various defense strategies to counter attacks from microorganisms or herbivores. For example, plants reduce the cell-wall-macerating activity of pathogen- or insect-derived polygalacturonases (PGs) by expressing PG-inhibiting proteins (PGIPs). PGs and PGIPs belong to multi-gene families believed to have been shaped by an evolutionary arms race. The mustard leaf beetle Phaedon cochleariae expresses both active PGs and catalytically inactive PG pseudoenzymes. Previous studies demonstrated that (i) PGIPs target beetle PGs and (ii) the role of PG pseudoenzymes remains elusive, despite having been linked to the pectin degradation pathway. For further insight into the interaction between plant PGIPs and beetle PG family members, we combined affinity purification with proteomics and gene expression analyses, and identified novel inhibitors of beetle PGs from Chinese cabbage (Brassica rapa ssp. pekinensis). A beetle PG pseudoenzyme was not targeted by PGIPs, but instead interacted with PGIP-like proteins. Phylogenetic analysis revealed that PGIP-like proteins clustered apart from classical PGIPs but together with proteins, which have been involved in developmental processes. Our results indicate that PGIP-like proteins represent not only interesting novel PG inhibitor candidates in addition to classical PGIPs, but also fascinating new players in the arms race between herbivorous beetles and plant defenses.

2021-06-07 | PXD022562 | Pride

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