Elevated levels of Protein S in Multiple Myeloma bone marrow microenvironment regulate tumor progression and bone disease

Abstract

The TAM (TYRO3, AXL, and MERTK) family of receptor tyrosine kinases exhibit cell-transforming capacity promoting tumorigenesis, metastasis and therapy-resistance in various cancer entities. GAS6-MERTK axis represents a target in Multiple Myeloma (MM) to inhibit tumor progression. We sought to explore the role of the alternative TAM receptor ligand Protein S (PROS1) in MM. Whereas PROS1 gene was not expressed by majority of MM plasma cells in a clinical cohort, PROS1 protein levels were increased in bone marrow (BM) plasma samples of MM patients. We could identify a negative regulatory function of PROS1 in MM plasma cells. Treatment of MM cells with PROS1 inhibited MM growth in vitro and PROS1 overexpression in U266 cell line inhibited MM progression in vivo. PROS1 upregulated AXLleading to an adhesive and quiescent myeloma cell phenotype in vitro, suggesting BM retention of MM plasma cells in vivo by PROS1-AXL axis. In addition to directly regulating myeloma plasma cell features, PROS1 interweaves with the disease-promoting myeloma BM microenvironment. We identified an IL-6–PROS1 crosstalk between osteoblasts and MM cells leading to inflammatory IL-6 cytokine signaling in osteoblasts via regulation of SOCS expression. Moreover, PROS1 promoted osteoclast differentiation of BM macrophages via increased SOCS - mediated inhibition of osteoclast - suppressive proinflammatory IL-6 signaling in BM macrophages. Enforced expression of PROS1 in MM plasma cells led to severe osteolytic bone destruction in mice, induced by increased osteoclast formation and suppression of osteoblasts, strengthening the rational for MERTK as a pharmacological target for myeloma bone disease independently from MM tumor burden.