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Stephen S Phillips, Gustav Stålhammar, Thonnie Rose See, Hans E Grossniklaus; Subpopulations of uveal melanoma cells have distinct roles and cooperate to promote hematogenous dissemination. Invest. Ophthalmol. Vis. Sci. 2019;60(9):959.
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© ARVO (1962-2015); The Authors (2016-present)
Uveal melanoma (UM) disseminates via hematogenous spread and ultimately results in mortality in 40-50% of patients. Loss of the tumor suppressor BRCA1 associated protein 1 (BAP1), presence of vasculogenic mimicry (VM), and gene expression profiling (GEP) all correlate with poor prognosis. Here, we connect these features and investigate the individual roles of different tumor cell subpopulations in UM.
Primary tumor samples from 30 patients that underwent enucleation for UM were stained using immunofluorescence with CD271, BAP1, laminin-5, VEGF, and CD34; using immunohistochemistry (IHC) with BAP1, melan A, CD31, and collagen-6; and with periodic-acid Schiff (PAS) without counterstain. Retrospective clinicopathological, gene expression, and survival data was collected. Additionally, real-time imaging of co-cultured BAP1 wild type and mutant 3D tumor spheroid invasion assays was examined with confocal microscopy.
VM patterns consisting of networks, closed loops, or arcs with branching were identified in 2 of 7 (29%) GEP class 1a tumors, 3 of 8 class (38%) 1b tumors, and 12 of 14 (86%) class 2 tumors. The presence of one or several of these three patterns within a tumor correlated strongly with GEP class 2 (Chi-square=7.3, p=0.018). Flattened and transdifferentiated BAP1 wild type cells were found to line VM channels. In tumors where most cells were BAP1 mutants, more advanced types of VM were identified (closed loops), which was associated with GEP class 2 (Fisher’s exact test p=0.021). BAP1 mutant cells expressed CD271 consistent with cancer stem cells (CSCs). VM patterns indicate a Cox regression metastasis-free survival on par with GEP class 2 when corrected for tumor size and are independent predictors of metastasis compared to GEP and BAP1 IHC. Examination of real-time migration of UM cells showed that transdifferentiated BAP1 wild type cells participated in the formation of VM patterns in the presence of BAP1 mutants.
Formation of VM and subsequent promotion of hematogenous dissemination occurs as an intricate interplay between BAP1 wild type and mutant UM cells.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
Patterns of vasculogenic mimicry and expression of BAP1 and CD271 in non-metastatic (left) and metastatic (right) tumors.
Cox regression, metastasis-free survival with (red) and without (blue) presence of vasculogenic mimicry, adjusted for tumor thickness.
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