Therapeutic targeting of tetraspanin8 in epithelial ovarian cancer invasion and metastasis

Cs, Park; Kim, TK; Hg, Kim; Kim, Yoon Jun; Mh, Jeoung; Lee, William R.; Nk, Go; Heo, Kyu; S, Lee

doi:10.1038/onc.2015.520

Cited by 58 publications

(52 citation statements)

References 27 publications

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“…Indeed, targeting Tspan8 to switch from a “non-sticky” to a “sticky” state may provide a means to prevent the spread of aggressive cells and thus, metastasis. This strategy is consistent with recent data identifying Tspan8 as a blood biomarker candidate for early detection of human colon cancer [54], and demonstrating that Tspan8-specific antibodies reduce the incidence of ovarian cancer metastasis [55]. …”

Section: Discussionsupporting

confidence: 90%

Tetraspanin 8 is a novel regulator of ILK-driven β1 integrin adhesion and signaling in invasive melanoma cells

et al. 2017

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Melanoma is well known for its propensity for lethal metastasis and resistance to most current therapies. Tumor progression and drug resistance depend to a large extent on the interplay between tumor cells and the surrounding matrix. We previously identified Tetraspanin 8 (Tspan8) as a critical mediator of melanoma invasion, whose expression is absent in healthy skin. The present study investigated whether Tspan8 may influence cell-matrix anchorage and regulate downstream molecular pathways leading to an aggressive behavior. Using silencing and ectopic expression strategies, we showed that Tspan8-mediated invasion of melanoma cells resulted from defects in cell-matrix anchorage by interacting with β1 integrins and by interfering with their clustering, without affecting their surface or global expression levels. These effects were associated with impaired phosphorylation of integrin-linked kinase (ILK) and its downstream target Akt-S473, but not FAK. Specific blockade of Akt or ILK activity strongly affected cell-matrix adhesion. Moreover, expression of a dominant-negative form of ILK reduced β1 integrin clustering and cell-matrix adhesion. Finally, we observed a tumor-promoting effect of Tspan8 in vivo and a mutually exclusive expression pattern between Tspan8 and phosphorylated ILK in melanoma xenografts and human melanocytic lesions. Altogether, the in vitro, in vivo and in situ data highlight a novel regulatory role for Tspan8 in melanoma progression by modulating cell-matrix interactions through β1 integrin-ILK axis and establish Tspan8 as a negative regulator of ILK activity. These findings emphasize the importance of targeting Tspan8 as a means of switching from low- to firm-adhesive states, mandatory to prevent tumor dissemination.

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Section: Discussionsupporting

confidence: 90%

Tetraspanin 8 is a novel regulator of ILK-driven β1 integrin adhesion and signaling in invasive melanoma cells

et al. 2017

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“…29,43 Two interesting novel genes had strong association (concurrent) with BDH and lower induction by CCl 4 (which causes fibrosis without BDH) relative to BDH-inducing treatments (Supplementary Figure S5): Tspan8 (rank 1 genomewide, p-adj = 2e − 35, effect size = 4.6) and Sox4 (rank 10, padj = 1e − 27; effect size = 3.0; Supplementary Table S8). Tspan8 is overexpressed and prognostic of survival in several cancers, [44][45][46] regulates cell adhesion and promotes migration. 47 It has measurable protein expression in normal human biliary epithelial cells, 48 and was identified in GWAS studies for type 2 diabetes.…”

Section: Resultsmentioning

confidence: 99%

Toxicogenomic module associations with pathogenesis: a network-based approach to understanding drug toxicity

et al. 2017

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Despite investment in toxicogenomics, nonclinical safety studies are still used to predict clinical liabilities for new drug candidates. Network-based approaches for genomic analysis help overcome challenges with whole-genome transcriptional profiling using limited numbers of treatments for phenotypes of interest. Herein, we apply co-expression network analysis to safety assessment using rat liver gene expression data to define 415 modules, exhibiting unique transcriptional control, organized in a visual representation of the transcriptome (the 'TXG-MAP'). Accounting for the overall transcriptional activity resulting from treatment, we explain mechanisms of toxicity and predict distinct toxicity phenotypes using module associations. We demonstrate that early network responses complement traditional histology-based assessment in predicting outcomes for longer studies and identify a novel mechanism of hepatotoxicity involving endoplasmic reticulum stress and Nrf2 activation. Module-based molecular subtypes of cholestatic injury derived using rat translate to human. Moreover, compared to gene-level analysis alone, combining module and gene-level analysis performed in sequence identifies significantly more phenotype-gene associations, including established and novel biomarkers of liver injury.

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“…Immunohistochemistry was performed as described previously with minor modifications [23]. Briefly, tissue slides printed with normal lung or lung cancer tissues were purchased from SuperBioChips Laboratories (Seoul, Korea).…”

Section: Methodsmentioning

confidence: 99%

A Human Antibody That Binds to the Sixth Ig-Like Domain of VCAM-1 Blocks Lung Cancer Cell Migration In Vitro

Kim

Jang

Park

et al. 2017

IJMS

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Vascular cell adhesion molecule-1 (VCAM-1) is closely associated with tumor progression and metastasis. However, the relevance and role of VCAM-1 in lung cancer have not been clearly elucidated. In this study, we found that VCAM-1 was highly overexpressed in lung cancer tissue compared with that of normal lung tissue, and high VCAM-1 expression correlated with poor survival in lung cancer patients. VCAM-1 knockdown reduced migration of A549 human lung cancer cells into Matrigel, and competitive blocking experiments targeting the Ig-like domain 6 of VCAM-1 (VCAM-1-D6) demonstrated that the VCAM-1-D6 domain was critical for VCAM-1 mediated A549 cell migration into Matrigel. Next, we developed a human monoclonal antibody specific to human and mouse VCAM-1-D6 (VCAM-1-D6 huMab), which was isolated from a human synthetic antibody library using phage display technology. Finally, we showed that VCAM-1-D6 huMab had a nanomolar affinity for VCAM-1-D6 and that it potently suppressed the migration of A549 and NCI-H1299 lung cancer cell lines into Matrigel. Taken together, these results suggest that VCAM-1-D6 is a key domain for regulating VCAM-1-mediated lung cancer invasion and that our newly developed VCAM-1-D6 huMab will be a useful tool for inhibiting VCAM-1-expressing lung cancer cell invasion.

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Therapeutic targeting of tetraspanin8 in epithelial ovarian cancer invasion and metastasis

Cited by 58 publications

References 27 publications

Tetraspanin 8 is a novel regulator of ILK-driven β1 integrin adhesion and signaling in invasive melanoma cells

Tetraspanin 8 is a novel regulator of ILK-driven β1 integrin adhesion and signaling in invasive melanoma cells

Toxicogenomic module associations with pathogenesis: a network-based approach to understanding drug toxicity

A Human Antibody That Binds to the Sixth Ig-Like Domain of VCAM-1 Blocks Lung Cancer Cell Migration In Vitro

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