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Published on: September 30, 2016
ADAM10 Knockout from Human Glioblastoma and Colon Cancer Cells Modulates Diverse Signalling Networks and Inhibits
Hengkang Yan1,2, Sakshi Arora1,2, Linda Hii3
1Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia.
Abstract:
ADAM10 is a transmembrane metalloprotease that regulates diverse signalling functions via the shedding of membrane protein ectodomains, and is implicated in tumour development, including glioblastoma multiforme (GBM) and gastrointestinal (GI) cancers, where high ADAM10 expression is associated with poor prognosis. We assessed the role of ADAM10 by gene knockout (KO) in U251 GBM cells, and its effects on protein shedding and protein expression on cell proliferation and on the growth of tumour xenografts in mice. The growth of tumours was severely delayed, relative to modest effects on proliferation in vitro, suggesting roles particularly in the context of the tumour microenvironment (TME). Proteomics analysis of KO cell-conditioned medium showed decreased levels of known ADAM10 targets such as Notch and Eph receptors and ligands, as well as other proteins involved in cell-cell adhesion, migration, signalling, metabolism, differentiation, and development, including angiogenesis. KO cell and tumour lysate analysis also showed modulation of proteins associated with metabolic and catalytic activity, cell-matrix organisation and differentiation. Similar effects were also observed in the SW620 colon cancer model, indicating broader significance. Furthermore, expression of the associated protein sets also correlated with ADAM10 expression in human GBM and colon cancer specimens (TCGA datasets), indicating clinical relevance. Collagens and proteins associated with matrix deposition and fibril organisation were notably reduced in ADAM10 KO GBM tumours, and histology confirmed decreased collagen fibrils and blood vessels. Unexpectedly, increased chondrocyte differentiation was evident in ADAM10 KO U251 tumours, suggesting a role for ADAM10 in maintaining an undifferentiated phenotype in vivo. Together, our data indicate the importance of ADAM10 in diverse signalling mechanisms in tumours and the TME that promote tumour development.
Insights
ADAM10 (a metalloprotease) is crucial for glioblastoma and colon cancer growth by influencing the tumor microenvironment. Gene knockout severely delayed tumor growth, highlighting ADAM10
Area of Science:
- Molecular Biology
- Cancer Research
- Biochemistry
Background:
- ADAM10 is a metalloprotease involved in shedding membrane proteins, impacting cell signaling.
- High ADAM10 expression correlates with poor prognosis in glioblastoma multiforme (GBM) and gastrointestinal (GI) cancers.
- ADAM10's role in tumor development and the tumor microenvironment (TME) requires further investigation.
Purpose of the Study:
- To investigate the function of ADAM10 in GBM and colon cancer models.
- To assess the impact of ADAM10 gene knockout (KO) on tumor growth, protein shedding, and expression.
- To explore the clinical relevance of ADAM10 and its associated protein sets in human cancers.
Main Methods:
- Gene knockout (KO) of ADAM10 in U251 GBM and SW620 colon cancer cells.
- Assessment of cell proliferation, tumor xenograft growth in mice, and protein shedding.
- Proteomics analysis of conditioned medium and cell/tumor lysates.
- Analysis of human GBM and colon cancer patient data (TCGA).
Main Results:
- ADAM10 KO severely delayed tumor xenograft growth, with modest effects on in vitro proliferation, suggesting a key role in the TME.
- Proteomics revealed decreased levels of known ADAM10 targets (e.g., Notch, Eph receptors) and proteins involved in cell adhesion, migration, signaling, metabolism, angiogenesis, and cell-matrix organization.
- ADAM10 KO tumors showed reduced collagen and blood vessels, but increased chondrocyte differentiation, indicating ADAM10's role in maintaining an undifferentiated phenotype.
- Results in GBM and colon cancer models were consistent, and protein set correlations with ADAM10 expression were observed in human cancer specimens.
Conclusions:
- ADAM10 plays a significant role in tumor development and the TME across different cancer types.
- ADAM10 influences diverse signaling pathways, including those regulating cell-matrix interactions, angiogenesis, and differentiation.
- Targeting ADAM10 may offer a therapeutic strategy for GBM and other cancers.
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