EDNRA-Expressing Mesenchymal Cells Are Expanded in Myeloma Interstitial Bone Marrow and Associated with Disease Progression

SIMPLE SUMMARY: In multiple myeloma, malignant plasma cells accumulate in the bone marrow. The symptoms and complications include osteolytic bone disease, anemia, reduced kidney function, immunosuppression, and induction of tumor-associated angiogenesis. Mesenchymal cells are important components of bone marrow niches; studying their dysfunctional activities reveals key features in myeloma pathogenies and improves therapies. We discovered that a subset of mesenchymal cells that express the receptor EDNRA are more prevalent in bone marrow areas infiltrated with tumor cells. In normal conditions, these cells are attached to blood vessels and mediate their functions; but in myeloma they seem to detach and accumulate in the interstitial marrow. The proportion of EDNRA-expressing cells and the expression of EDNRA in bone biopsies is low in premalignant stages and highest in high-risk myeloma patients. EDNRA could serve as a useful novel clinical biomarker of disease progression and dysfunctional bone marrow vasculature. ABSTRACT: Multiple myeloma (MM) induces dysfunctional bone marrow (BM) mesenchymal cells and neoangiogenesis. Pericytes and smooth muscle cells (SMCs) could detach from vessels and become cancer-associated fibroblasts. We found that the pericyte and SMC marker endothelin receptor type A (EDNRA) is overexpressed in whole MM bone biopsies; we sought to characterize its expression. EDNRA expression gradually increased with disease progression. High-risk MM patients had higher EDNRA expression than low-risk MM patients and EDNRA expression was highest in focal lesions. High EDNRA expression was associated with high expression of pericyte markers (e.g., RGS5, POSTN, and CD146) and the angiogenic marker FLT1. A single-cell analysis of unexpanded BM mesenchymal cells detected EDNRA expression in a subset of cells that coexpressed mesenchymal cell markers and had higher expression of proliferation genes. Immunohistochemistry revealed that the number of EDNRA+ cells in the interstitial BM increased as MM progressed; EDNRA+ cells were prevalent in areas near the MM focal growth. EDNRA+ cells were detached from CD34+ angiogenic cells and coexpressed RGS5 and periostin. Therefore, they likely originated from pericytes or SMCs. These findings identify a novel microenvironmental biomarker in MM and suggest that the presence of detached EDNRA+ cells indicates disrupted vasculature and increased angiogenesis.