Abstract
Purpose :
Uveal melanoma (UM) is the most common primary tumor in the eye of adults. Using gene expression profiling, UM can be stratified into two main classes based on metastatic risk. Class 2 UM has a high metastatic risk and is notoriously difficult to treat and resistant to conventional therapies. Virtually all Class 2 UM tumors display a loss of the BRCA1 associated protein-1 (BAP1) gene. Unlike metastatic cutaneous melanoma, which responds very well to checkpoint inhibitor immunotherapy, current treatment regimens for Class 2 UM have not yet yielded significant increases in survival. The metastatic potential and treatment-refractory properties of Class 2 UM are thought to result partially from the tumor’s ability to mimic physiologic processes that mitigate the immune response to achieve quasi-immunoprivilege. PROS1 acts as a paracrine anti-inflammatory effector of tumor-associated macrophages and has been shown to be upregulated in several different cancers (including pancreatic, lung, and breast). We tested the hypothesis that Class 2 UM express elevated levels of PROS1.
Methods :
In this study, differential gene expression of PROS1 was analyzed from RNASeq data collected from cell lysates of cultured human uveal melanoma cells and melanocytes following BAP1 depletion, and from publicly available RNASeq data of class 2 UM samples from The Cancer Genome Atlas (TCGA) registry. Protein levels of PROS1 from cell lysate of human uveal melanocytes with and without BAP1 knockout were measured by Western blot analysis.
Results :
RNASeq showed a 4 to 5-fold increase in PROS1 mRNA in the Class 2 UM and uveal melanocyte cell lines with BAP1 knockout. Western blot analysis also showed a stark increase in PROS1 protein expression in uveal melanocyte cell lines following BAP1 knockout.
Conclusions :
Our results are consistent with the hypothesis that Class 2 UM tumors express elevated levels of PROS1 and suggest that this pathway may represent one component of these tumors’ enhanced metastatic potential. PROS1 may represent a novel target for pharmacologic therapies versus Class 2 UM.
This is a 2020 ARVO Annual Meeting abstract.