期刊
ONCOTARGET
卷 7, 期 29, 页码 46492-46508出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.10216
关键词
melanoma; desmoglein 2; vasculogenic mimicry; cadherin; TCGA
资金
- RAH Research Fund Florey Fellowship
- veski and Pfizer Australia
- Heart Foundation Fellowship [CR 10A 4983]
- Lorenzo and Pamela Galli Charitable Trust
- NHMRC Program Grant [1053792]
- NHMRC [1022150]
- Cancer Council SA Beat Cancer Project grant
- NHMRC program grant
- Melbourne Melanoma Project
- Victoria Cancer Agency
- Victorian Institute of Forensic Medicine
- NHMRC Program Fellowships [1002654, 1106576]
- National Health and Medical Research Council of Australia [1106576] Funding Source: NHMRC
Tumors can develop a blood supply not only by promoting angiogenesis but also by forming vessel-like structures directly from tumor cells, known as vasculogenic mimicry (VM). Understanding mechanisms that regulate VM is important, as these might be exploitable to inhibit tumor progression. Here, we reveal the adhesion molecule desmoglein 2 (DSG2) as a novel mediator of VM in melanoma. Analysis of patient-derived melanoma cell lines and tumor tissues, and interrogation of The Cancer Genome Atlas (TCGA) data, revealed that DSG2 is frequently overexpressed in primary and metastatic melanomas compared to normal melanocytes. Notably, this overexpression was associated with poor clinical outcome. DSG2(+) melanoma cells self-organized into tube-like structures on Matrigel, indicative of VM activity, which was inhibited by DSG2 knockdown or treatment with a DSG2-blocking peptide. Mechanistic studies revealed that DSG2 regulates adhesion and cell-cell interactions during tube formation, but does not control melanoma cell viability, proliferation or motility. Finally, analysis of patient tumors revealed a correlation between DSG2 expression, VM network density and expression of VM-associated genes. These studies identify DSG2 as a key regulator of VM activity in human melanoma and suggest this molecule might be therapeutically targeted to reduce tumor blood supply and metastatic spread.
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