The growth and spread of solid tumours such as
melanoma is dependent on an ability to access the blood supply. To meet this
requirement, melanoma cells not only promote blood vessel sprouting
(angiogenesis) but can also form vessel-like structures themselves, a process
known as vasculogenic mimicry (VM). The presence of VM networks in primary
melanoma is tightly linked to increased metastasis and poor survival, suggesting
that targeting VM in the clinic holds enormous therapeutic potential. However,
the molecular mechanisms controlling this process are poorly understood. We
demonstrate here that desmoglein-2 (DSG2), an adhesion molecule belonging to
the desmosomal cadherin family, is ectopically expressed in human melanoma and
plays a critical role in regulating melanoma VM. Gene array analysis of 70
human melanoma cell lines revealed that DSG2 was frequently expressed by melanoma
cells, a finding confirmed by flow cytometry and Western blot. Moreover, analysis
of patient tumour tissue by immunohistochemistry and 4-colour
immunofluorescence revealed broad expression of DSG2 in primary and metastatic
melanoma. Tube formation assays revealed that the majority (5/6) of DSG2+
melanoma cell lines could self-organise into tube-like structures within 6hr of
seeding on Matrigel, indicative of a high level of VM activity. Notably, tube formation
was significantly inhibited in response to siRNA-mediated DSG2 knockdown or treatment with a DSG2-blocking peptide in three
different cell lines. Live imaging of the tube formation process revealed that
cell motility and shape change were significantly altered following DSG2 knockdown, suggesting novel roles
for DSG2 outside of its well-established function in desmosomal adhesion. Together,
these studies reveal DSG2 as a key regulator of melanoma VM activity, and
suggest that this molecule could be targeted to reduce tumour perfusion and
metastatic spread.