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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

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

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

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2018-09-14 | GSE119909 | GEO

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

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2023-10-14 | GSE245016 | GEO

Interaction of Chinese cabbage (Brassica rapa ssp. pekinensis) cell wall proteins with mustard leaf beetle (Phaedon cochleariae) polygalacturonase family members

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.

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