Oncotarget

Research Papers:

Desmoglein 2 promotes vasculogenic mimicry in melanoma and is associated with poor clinical outcome

Lih Yin Tan, Chris Mintoff, Zahied M. Johan, Brenton W. Ebert, Clare Fedele, You Fang Zhang, Pacman Szeto, Karen E. Sheppard, Grant A. McArthur, Erwin Foster-Smith, Andrew Ruszkiewicz, Michael P. Brown, Claudine S. Bonder, Mark Shackleton and Lisa M. Ebert _

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Oncotarget. 2016; 7:46492-46508. https://doi.org/10.18632/oncotarget.10216

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Abstract

Lih Yin Tan1,2, Chris Mintoff3, M. Zahied Johan1, Brenton W. Ebert1, Clare Fedele3, You Fang Zhang3, Pacman Szeto3, Karen E. Sheppard4,5, Grant A. McArthur4,5, Erwin Foster-Smith6, Andrew Ruszkiewicz6, Michael P. Brown1,7,8, Claudine S. Bonder1,*, Mark Shackleton3,5,*, Lisa M. Ebert1,*

1Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia

2School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia

3Cancer Development and Treatment Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

4Molecular Oncology Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

5Sir Peter MacCallum Department of Oncology and Department of Pathology, University of Melbourne, VIC, Australia

6Division of Anatomical Pathology, SA Pathology, Adelaide, SA, Australia

7Cancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, SA, Australia

8Discipline of Medicine, University of Adelaide, Adelaide, SA, Australia

*Co-senior author

Correspondence to:

Lisa M. Ebert, email: lisa.ebert@sa.gov.au

Keywords: melanoma, desmoglein 2, vasculogenic mimicry, cadherin, TCGA

Received: April 04, 2016     Accepted: June 03, 2016     Published: June 22, 2016

ABSTRACT

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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