Proteoglycans Determine the Dynamic Landscape of EMT and Cancer Cell Stemness

Karagiorgou, Zoi; Fountas, Panagiotis N.; Manou, Dimitra; Knutsen, Erik; Theocharis, Achilleas D.

doi:10.3390/cancers14215328

Cited by 9 publications

(4 citation statements)

References 159 publications

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“…HSPGs comprise of highly sulfated repeating disaccharide units ( 59 ), present on the cell surface and in the extracellular matrix ( 6 ). Due to their negative charge, the sulfated chains act as co-receptors, enhancing the interactions between ligands and their respective receptors ( 60 ).…”

Section: Discussionmentioning

confidence: 99%

“…Activation of this program triggers the transdifferentiation of carcinoma cells into a partially mesenchymal state ( 2 ), accompanied by profound changes in cellular physiology. These changes involve noticeable alterations in cell morphology, loss of cell–cell interactions ( 3 ), acquisition of migratory and invasive capabilities ( 4 ), development of chemoresistance ( 5 ), and remodeling of the proteoglycan landscape ( 6 ). Therefore, a deeper understanding of the cellular mechanisms mediating this program is crucial for advancing our comprehension of cancer biology and developing therapeutic strategies to impede its progression.…”

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confidence: 99%

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The exostosin glycosyltransferase 1/STAT3 axis is a driver of breast cancer aggressiveness

Solaimuthu,

Khatib,

Tanna

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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The epithelial–mesenchymal transition (EMT) program is crucial for transforming carcinoma cells into a partially mesenchymal state, enhancing their chemoresistance, migration, and metastasis. This shift in cell state is tightly regulated by cellular mechanisms that are not yet fully characterized. One intriguing EMT aspect is the rewiring of the proteoglycan landscape, particularly the induction of heparan sulfate proteoglycan (HSPG) biosynthesis. This proteoglycan functions as a co-receptor that accelerates cancer-associated signaling pathways through its negatively-charged residues. However, the precise mechanisms through which EMT governs HSPG biosynthesis and its role in cancer cell plasticity remain elusive. Here, we identified exostosin glycosyltransferase 1 (EXT1), a central enzyme in HSPG biosynthesis, to be selectively upregulated in aggressive tumor subtypes and cancer cell lines, and to function as a key player in breast cancer aggressiveness. Notably, ectopic expression of EXT1 in epithelial cells is sufficient to induce HSPG levels and the expression of known mesenchymal markers, subsequently enhancing EMT features, including cell migration, invasion, and tumor formation. Additionally, EXT1 loss in MDA-MB-231 cells inhibits their aggressiveness-associated traits such as migration, chemoresistance, tumor formation, and metastasis. Our findings reveal that EXT1, through its role in HSPG biosynthesis, governs signal transducer and activator of transcription 3 (STAT3) signaling, a known regulator of cancer cell aggressiveness. Collectively, we present the EXT1/HSPG/STAT3 axis as a central regulator of cancer cell plasticity that directly links proteoglycan synthesis to oncogenic signaling pathways.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

The exostosin glycosyltransferase 1/STAT3 axis is a driver of breast cancer aggressiveness

Solaimuthu,

Khatib,

Tanna

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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“…HSPGs are composed of highly sulfated repeating disaccharide units 56 found on the cell surface and in the extracellular matrix 5 . Due to their negative charge, the sulfated chains act as co-receptors, enhancing the interactions between ligand and their respective receptors 57 .…”

Section: Discussionmentioning

confidence: 99%

“…Upon activation, this program transdifferentiates the carcinoma cells into a partially mesenchymal state 2 , leading to significant changes in cellular physiology. This program includes notable morphological changes, loss of cell-cell interactions 3 , acquisition of migratory and invasive capabilities 4 , and remodeling the proteoglycan landscape 5 . Therefore, a deeper understanding of cellular mechanisms mediating this program may lead to an improved conceptualization of EMT biology and therapeutic strategies to block its progression.…”

Section: Introductionmentioning

confidence: 99%

The metabolic enzyme EXT1 is sufficient to induce the epithelial-mesenchymal transition program in cancers

Solaimuthu

Khatib

Hayashi

et al. 2023

Preprint

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Carcinomas often exhibit aggressive characteristics, such as enhanced migration abilities, through the execution of the epithelial-mesenchymal transition (EMT) program. Heparan sulfate (HS) is a polysaccharide expressed on the surface of aggressive cancer cells, which acts as a co-receptor to stimulate EMT-associated signaling pathways. However, despite HS role in cancer aggressiveness, the mechanisms governing its EMT-dependent biosynthesis remains poorly understood. Here, we characterized the HS chain elongation enzyme, exostosin glycosyltransferase 1 (EXT1), as an essential component of the EMT program. We identified an EMT-dependent expression of EXT1 and its selective upregulation in aggressive tumor subtypes and cell lines. Overexpression of EXT1 in epithelial cells is sufficient to induce HS biosynthesis, cell migration, and invasion, form tumors in mice, and activate the STAT3 pathway. Moreover, its knockout in aggressive cells significantly inhibited their EMT-associated characteristics. These findings demonstrate a cellular mechanism by which metabolic processes regulate signaling pathways to govern cell state.

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Expression of CD44 is associated with aggressiveness in seminomas

Labropoulou,

Manou,

Ravazoula

et al. 2024

Mol Biol Rep

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Background Testicular germ cell tumors (TGCTs) exhibit diverse biological and pathological features and are divided in two main types, seminomas and nonseminomatous germ cell tumors (NSGCTs). CD44 is a cell surface receptor, which is highly expressed in malignancies and is implicated in tumorigenesis affecting cell-matrix interactions and cell signaling. Methods and results Here, we examined the expression of CD44 in tumor cell lines and in patients’ material. We found that CD44 is over-expressed in TGCTs compared to normal tissues. Immunohistochemical staining in 71 tissue specimens demonstrated increased expression of CD44 in some patients, whereas CD44 was absent in normal tissue. In seminomas, a high percentage of tumor and stromal cells showed cytoplasmic and/or cell surface staining for CD44 as well as increased staining for CD44 in the tumor stroma was found in some cases. The increased expression of CD44 either in tumor cells or in stromal components was associated with tumor size, nodal metastasis, vascular/lymphatic invasion, and disease stage only in seminomas. The increased stromal expression of CD44 in TGCTs was positively associated with angiogenesis. Conclusions CD44 may exhibit diverse biological functions in seminomas and NSGCTs. The expression of CD44 in tumor cells as well as in tumor stroma fosters an aggressive phenotype in seminomas and should be considered in disease treatment.

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Proteoglycans Determine the Dynamic Landscape of EMT and Cancer Cell Stemness

Cited by 9 publications

References 159 publications

The exostosin glycosyltransferase 1/STAT3 axis is a driver of breast cancer aggressiveness

The exostosin glycosyltransferase 1/STAT3 axis is a driver of breast cancer aggressiveness

The metabolic enzyme EXT1 is sufficient to induce the epithelial-mesenchymal transition program in cancers

Expression of CD44 is associated with aggressiveness in seminomas

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