Formation of new blood vessels in a solid tumour are critical for cancer growth and metastasis. Until recently, tumour vasculature was thought to occur exclusively via angiogenesis using endothelial cells (ECs). However, there is now increasing evidence that many solid tumours are capable of creating an independent blood supply using the tumour cells themselves, a process known as vasculogenic mimicry (VM) which correlates with poor prognosis. We have identified the adhesion molecule desmoglein-2 (DSG2) as an important cadherin of the vasculature that promotes both angiogenesis and VM. Moreover, increased DSG2 expression correlates with poor outcome for patients with melanoma.
Herein we reveal that the VM capability of melanoma cells positively correlates with the adhesion/recruitment of peripheral blood mononuclear cells. Using the parallel plate flow chamber and transwell migration assays we observed that monocytes are selectively recruited across a melanoma cell monolayer via select adhesion molecules and chemokines. We observed that growth of the mouse melanoma cell line B16-F10-GFP-P2A-luc is significantly reduced in mice with loss-of-function Dsg2 (Dsg2lo/lo) when compared to control mice (WT) and mice wherein Dsg2 has been restored (Dsg2R/R). Histologically, tumours from Dsg2lo/lo mice reveal attenuated tumour vasculature, but increased high endothelial venule (HEV) content, increased cancer killing CD8+ T lymphocytes but reduced FoxP3+ Treg infiltrate.
Taken together our results suggest that Dsg2 plays an underappreciated role in regulating tumour vasculature and the infiltration of leukocytes. Ongoing investigations are underway to understand how modulating expression of Dsg2 can reshape the tumour vasculature for increased tumour infiltrating leukocytes and whether DSG2 is a potential target to treat melanoma, or possibly even support CAR-T cell therapy.