Organelle Specific O-Glycosylation Drives MMP14 Activation, Tumor Growth, and Metastasis

Nguyễn, Anh Tuấn; Chia, Joanne; Ros, Manon; Hui, Kam M.; Saltel, Frédéric; Bard, Frédéric

doi:10.1016/j.ccell.2017.10.001

Cited by 108 publications

(110 citation statements)

References 57 publications

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“…The association of cancer invasion with tumor growth and metastasis was indicated by recent lysosomal proteases studies, including research on MMP-3 39 , 45 , MT1-MMP 40 , 46 , cathepsin B 47 , 48 , and cathepsin D 49 . Due to the significant effect of Arl8b on highly invasive cancer cells that survive IR, we sought to validate whether Arl8b is required for invasive tumor growth and metastasis in a mouse model.…”

Section: Resultsmentioning

confidence: 99%

Lysosomal trafficking mediated by Arl8b and BORC promotes invasion of cancer cells that survive radiation

Onodera

Giaccia

et al. 2020

Commun Biol

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Enhanced invasiveness, a critical determinant of metastasis and poor prognosis, has been observed in cancer cells that survive cancer therapy, including radiotherapy. Here, we show that invasiveness in radiation-surviving cancer cells is associated with alterations in lysosomal exocytosis caused by the enhanced activation of Arl8b, a small GTPase that regulates lysosomal trafficking. The binding of Arl8b with its effector, SKIP, is increased after radiation through regulation of BORC-subunits. Knockdown of Arl8b or BORC-subunits decreases lysosomal exocytosis and the invasiveness of radiation-surviving cells. Notably, high expression of ARL8B and BORC-subunit genes is significantly correlated with poor prognosis in breast cancer patients. Sp1, an ATM-regulated transcription factor, is found to increase BORC-subunit genes expression after radiation. In vivo experiments show that ablation of Arl8b decreases IR-induced invasive tumor growth and distant metastasis. These findings suggest that BORC-Arl8b-mediated lysosomal trafficking is a target for improving radiotherapy by inhibiting invasive tumor growth and metastasis.

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Section: Resultsmentioning

confidence: 99%

Lysosomal trafficking mediated by Arl8b and BORC promotes invasion of cancer cells that survive radiation

Onodera

Giaccia

et al. 2020

Commun Biol

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“…MMPs are abundantly detected in numerous malignant neoplasms and have critical implications in almost all stages of tumour progression [2]. Recent studies have shown that aberrant MMP expression is associated with the invasion and metastasis of several malignant tumours (colorectal [3], prostate [4], liver [5], breast [6], retinoblastoma [7], and lung [8]) both in vitro and vivo. Among the MMPs, MMP7 (aka matrilysin1) is the smallest secreted proteolytic enzyme, lacking the C-terminal hemopexin domain compared with other family members, with a wide spectrum of substrate specificity against ECM components, including laminin, type IV collagen, fibronectin, and proteoglycans [9,10], as well as other molecules, such as E-cadherin, β4 integrin, tumour necrosis factor-α, and the Fas ligand [11].…”

Section: Introductionmentioning

confidence: 99%

Elevated matrix metalloproteinase 7 expression promotes the proliferation, motility and metastasis of tongue squamous cell carcinoma

et al. 2020

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Background: Matrix metalloproteinase 7 (MMP7), as the smallest member of the matrix metalloproteinase family, has been verified to be implicated in cancer progression, especially metastasis. However, its expression pattern and function in tongue cancer is not clear. Methods: The expression of MMP7 in human tongue squamous cell carcinoma (TSCC) specimens compared with their respective paired nontumour tissues by real-time PCR and immunohistochemical staining. The effect of MMP7 on the proliferation, apoptosis, migration, invasion of tongue cancer cells was tested in appropriate ways after MMP7 siRNA knockdown or overexpression. The effect of MMP7 on lymph node metastasis in vivo was analyzed using a high-metastasis orthotopic nude mouse tongue transplanted tumour model. Results: We found markedly elevated expression of MMP7 in human TSCC specimens compared with their respective paired nontumour tissues, and this high expression was correlated with the patients' lymph node metastasis. Furthermore, the results of molecular functional assays confirmed that MMP7 promotes cell proliferation, migration and invasion of TSCC cells. Knockdown of MMP7 inhibited lymph nodes metastasis in vivo. Conclusions: MMP7 plays an oncogenic role in carcinogenesis and metastasis of tongue cancer, and may serve as a potential therapeutic target for tongue cancer.

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“…In this scenario, the maturation process may orchestrate the glycosylation pathways to change glycosylation patterns according to functional needs, and may therefore also, in case of malfunctions, cause glycosylation imbalances that lead to disease, including cancer. Thus, the altered glycosylation frequently associated with cancer might both result from, and contribute to, the pathological signaling patterns typical of this disease Nguyen et al, 2017;Pinho and Reis, 2015;Stanley, 2011;Stowell et al, 2015). Our data suggest that the identification of the recycling mechanisms operating on the various enzyme modules and of the associated regulatory mechanisms will contribute significantly to our understanding of the role of Golgi dynamics in physiology and pathology.…”

Section: Discussionmentioning

confidence: 76%

The Glyco-enzyme adaptor GOLPH3 Links Intra-Golgi Transport Dynamics to Glycosylation Patterns and Cell Proliferation

Rizzo

Russo

Kurokawa

et al. 2019

Preprint

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Glycans are ubiquitous sugar polymers with major biological functions that are assembled by glyco-enzymes onto cargo molecules during their transport through the Golgi complex. How the Golgi determines glycan assembly is poorly understood. By relying on the Golgi cisternal maturation model and using the glyco-enzyme adaptor and oncoprotein GOLPH3 as a molecular tool, we define the first example of how the Golgi controls glycosylation and associated cell functions. GOLPH3, acting as a component of the cisternal maturation mechanism, selectively binds and recycles a subset of glyco-enzymes of the glycosphingolipid synthetic pathway, hinders their escape to the lysosomes and hence increases their levels through a novel lysosomal degradation-regulated mechanism. This enhances the production of specific growth-inducing glycosphingolipids and reprograms the glycosphingolipid pathway to potentiate mitogenic signaling and cell proliferation. These findings unravel unforeseen organizing principles of Golgi-dependent glycosylation and delineate a paradigm for glycan assembly by the Golgi transport mechanisms. Moreover, they indicate a new role of cisternal maturation as a regulator of glycosylation, and outline a novel mechanism of action for GOLPH3-induced proliferation.

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Organelle Specific O-Glycosylation Drives MMP14 Activation, Tumor Growth, and Metastasis

Cited by 108 publications

References 57 publications

Lysosomal trafficking mediated by Arl8b and BORC promotes invasion of cancer cells that survive radiation

Lysosomal trafficking mediated by Arl8b and BORC promotes invasion of cancer cells that survive radiation

Elevated matrix metalloproteinase 7 expression promotes the proliferation, motility and metastasis of tongue squamous cell carcinoma

The Glyco-enzyme adaptor GOLPH3 Links Intra-Golgi Transport Dynamics to Glycosylation Patterns and Cell Proliferation

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