title: Desmoglein 2 promotes vasculogenic mimicry in melanoma and is associated with poor clinical outcome.
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.
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia.|School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia.
authors.forename: Lih Yin
authors.initials: LY
authors.lastname: Tan
authors.affiliation: Cancer Development and Treatment Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
authors.forename: Chris
authors.initials: C
authors.lastname: Mintoff
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia.
authors.forename: M Zahied
authors.initials: MZ
authors.lastname: Johan
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia.
authors.forename: Brenton W
authors.initials: BW
authors.lastname: Ebert
authors.affiliation: Cancer Development and Treatment Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
authors.forename: Clare
authors.initials: C
authors.lastname: Fedele
authors.affiliation: Cancer Development and Treatment Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
authors.forename: You Fang
authors.initials: YF
authors.lastname: Zhang
authors.affiliation: Cancer Development and Treatment Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
authors.forename: Pacman
authors.initials: P
authors.lastname: Szeto
authors.affiliation: Molecular Oncology Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.|Sir Peter MacCallum Department of Oncology and Department of Pathology, University of Melbourne, VIC, Australia.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Sheppard
authors.affiliation: Molecular Oncology Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.|Sir Peter MacCallum Department of Oncology and Department of Pathology, University of Melbourne, VIC, Australia.
authors.forename: Grant A
authors.initials: GA
authors.lastname: McArthur
authors.affiliation: Division of Anatomical Pathology, SA Pathology, Adelaide, SA, Australia.
authors.forename: Erwin
authors.initials: E
authors.lastname: Foster-Smith
authors.affiliation: Division of Anatomical Pathology, SA Pathology, Adelaide, SA, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Ruszkiewicz
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia.|Cancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, SA, Australia.|Discipline of Medicine, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Brown
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia.
authors.forename: Claudine S
authors.initials: CS
authors.lastname: Bonder
authors.affiliation: Cancer Development and Treatment Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.|Sir Peter MacCallum Department of Oncology and Department of Pathology, University of Melbourne, VIC, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Shackleton
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Ebert
mesh_terms: D002448:Cell Adhesion; D045744:Cell Line, Tumor; D051301:Desmoglein 2 / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D003937:Diagnosis, Differential; D006801:Humans; D008544:Melanocytes / Q000737:chemistry; D008545:Melanoma / Q000098:blood supply* / Q000737:chemistry / Q000188:drug therapy / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000209:etiology*; D017423:Sequence Analysis, RNA
chemical_list: C495314:DSG2 protein, human; D051301:Desmoglein 2
keywords: TCGA; cadherin; desmoglein 2; melanoma; vasculogenic mimicry