A disintegrin and metalloproteinases 10 and 17 modulate the immunogenicity of glioblastoma-initiating cells

Wolpert, Fabian; Tritschler, Isabel; Steinle, Alexander; Weller, Michael; Eisele, Günter

doi:10.1093/neuonc/not232

Cited by 52 publications

(52 citation statements)

References 34 publications

(51 reference statements)

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“…Wolpert et al demonstrated that NKG2dL mRNA and surface expression levels may differ, which is most likely due to posttranslational and posttranscriptional modification (69). Other mechanisms, including the induction of surface loss of MIcB via the secretory pathway by human cytomegalovirus, may also serve a role (70,71) in this process.…”

Section: Discussionmentioning

confidence: 99%

Dormancy and NKG2D system in brain�metastases: Analysis of immunogenicity

Flüh¹,

Mafael²,

Adamski³

et al. 2019

Int J Mol Med

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Patients with breast cancer (Bc) and lung cancer (Lc) are prone to developing brain metastases, which are associated with devastating prognoses. dormant tumor cells, a population of non-apoptotic quiescent cells and immunological escape mechanisms, including the Natural Killer Group 2 member d (NKG2d) receptor-ligand system, represent potential mechanisms of tumor recurrence. To date, the immunological characteristics of dormant tumor cells concerning the NKG2d system in cerebral malignancies are mostly unknown. In the present study, an extensive characterization of dormant and NKG2d ligand (NKG2dL) + cells in cerebral metastases was performed. The expression profiles and localization patterns of various NKG2dL and several dormancy markers were analyzed in solid human brain metastases from patients with Bc and Lc using immunostaining and reverse transcription-quantitative polymerase chain reaction analyses. Statistical analysis was performed using Student's t-test and Bravais-Pearson correlation analysis. Not only 'peripheral', but also 'central' dormancy markers, which had been previously described in primary brain tumors, were identified in all cerebral metastases at detectable levels at protein and mRNA levels. Notably, the majority of NKG2dL + cells were also positive for 'central' dormancy markers, but not 'peripheral' dormancy markers in both patient groups. This cell population may represent a promising future therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Dormancy and NKG2D system in brain�metastases: Analysis of immunogenicity

Flüh¹,

Mafael²,

Adamski³

et al. 2019

Int J Mol Med

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“…Increased Acts as a sheddase for membrane-bound molecules such as N-CAM (Kohutek et al 2009), CD44 (Murai et al 2004), L1CAM (Mohanan et al 2013), CXCL16 (Ludwig et al 2005), and Coxsackievirus and Adenovirus Receptor (CAR) (Houri et al 2013), thereby promoting glioma motility and growth; important for the renewal of glioma stem-like cells (Bulstrode et al 2012); involved in the impaired immune recognition of glioma stem cells (Wolpert et al 2014). …”

Section: Adam10mentioning

confidence: 99%

“…Ambiguous data Decreased expression reported by Comincini et al (2009), increased according to TCGA data; mediates hypoxia-induced glioma invasiveness (Zheng et al 2007); may contribute to stemness maintenance through the Notch signaling ); promotes the malignant phenotype of glioma cells ); introduction into astrocytes induced a neoplastic phenotype by deregulating EGFR signaling ); involved in the impaired immune recognition of glioma stem cells (Wolpert et al 2014). …”

Section: Adam17mentioning

confidence: 99%

“…Their substrates include structural protein components of the extracellular matrix (ECM), zymogens of other proteases, and regulatory molecules such as chemokines, cytokines, and cell surface receptors or plasma membranebound proteins that may be released into the extracellular space ( Fig. Finally, by shedding cell surface molecules responsible for the activation of the immune system such as NKG2D ligands (Eisele et al 2006;Wolpert et al 2014) and activating latent TGF-β (Huber et al 1992;Leitlein et al 2001), proteases aid glioma cells to escape from the immune surveillance. These proteases therefore frequently serve as direct (e.g., via protease-activated receptors) or indirect (e.g., by modifying or releasing signaling molecules) mediators of intercellular communication.…”

Section: Protease-mediated Protein Processing In Gliomas and Participmentioning

confidence: 99%

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Glioma Cell Biology

Šedo¹,

Mentlein²

2014

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“…This also causes a release of trophic factors to stimulate tumor growth, dispersal, and modulation of inflammatory responses. Members of the A Disintegrin and Metalloproteinase (ADAM) family of zinc-dependent proteinases contribute to GBM therapeutic resistance and invasiveness (15,16), as well as to the regulation of GSCs (17)(18)(19). ADAMDEC1 is a soluble member of this family that is novel in mammals.…”

Section: Introductionmentioning

confidence: 99%

ADAMDEC1 maintains a novel growth factor signaling loop in cancer stem cells

Hale

Jimenez-Pascual

Kordowski

et al. 2019

Preprint

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Glioblastomas (GBM) are lethal brain tumors where poor outcome is attributed to cellular heterogeneity, therapeutic resistance, and a highly infiltrative nature. These characteristics are preferentially linked to GBM cancer stem cells (GSCs), but how GSCs maintain their stemness is incompletely understood and the subject of intense investigation. Here, we identify a novel signaling loop that induces and maintains GSCs. This loop consists of an atypical metalloproteinase, a disintegrin and metalloproteinase domain-like protein decysin 1 (ADAMDEC1), secreted by GSCs. ADAMDEC1 rapidly solubilizes fibroblast growth factor-2 (FGF2) to stimulate FGF receptor 1 (FGFR1) expressed on GSCs. This signaling axis induces upregulation of Zinc finger E-box-binding homeobox 1 (ZEB1) that regulates ADAMDEC1 expression, creating a positive feedback loop. Genetic or pharmacological targeting of components of this axis attenuates self-renewal and tumor growth. These findings reveal a new signaling axis for GSC maintenance and highlight ADAMDEC1 and FGFR1 as potential therapeutic targets in GBM. Statement of SignificanceCancer stem cells (CSC) drive tumor growth in many cancers including glioblastoma. We identified a novel sheddase, a disintegrin and metalloproteinase domain-like protein decysin 1, that initiates a fibroblast growth factor autocrine loop to promote stemness in CSCs. This loop can be targeted to reduce glioblastoma growth.

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A disintegrin and metalloproteinases 10 and 17 modulate the immunogenicity of glioblastoma-initiating cells

Abstract: Therefore, ADAM10 and ADAM17 constitute suitable targets to boost an immune response against GIC.

Cited by 52 publications

References 34 publications

Dormancy and NKG2D system in brain�metastases: Analysis of immunogenicity

Dormancy and NKG2D system in brain�metastases: Analysis of immunogenicity

Glioma Cell Biology

ADAMDEC1 maintains a novel growth factor signaling loop in cancer stem cells

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