Role of BRAF^sup V600E^ in the First Preclinical Model of Multifocal Infiltrating Myopericytoma Development and Microenvironment

Myopericytoma (MPC) is a rare tumor with perivascular proliferation of pluripotent stem-cell-like pericytes. Although indolent, MPC may be locally aggressive with recurrent disease. The pathogenesis and diagnostic biomarkers of MPC are poorly understood. We discovered that 15% of benign MPCs (thyroid, skin; 3 of 20 samples) harbored BRAF...; 33.3% (1 of 3 samples) of BRAF...-MPCs were multifocal/infiltrative/recurrent. Patient-MPC and primary MPC cells harbored BRAF..., were clonal and expressed pericytic-differentiation biomarkers crucial for its microenvironment. BRAF...-positive thyroid MPC primary cells triggered in vitro (8.8-fold increase) and in vivo (3.6-fold increase) angiogenesis. Anti-BRAF... therapy with vemurafenib disrupted angiogenic and metabolic properties (~3-fold decrease) with down-regulation (~2.2-fold decrease) of some extracellular-matrix (ECM) factors and ECM-associated long non-coding RNA (LincRNA) expression, with no effects in BRAF...-pericytes. Vemurafenib also inhibited (~3-fold decrease) cell viability in vitro and in BRAF...-positive thyroid MPC patient-derived xenograft (PDX) mice (n = 5 mice per group). We established the first BRAF...-dependent thyroid MPC cell culture. Our findings identify BRAF... as a novel genetic aberration in MPC pathogenesis and MPC-associated biomarkers and imply that anti-BRAF... agents may be useful adjuvant therapy in BRAF...-MPC patients. Patients with BRAF...-MPC should be closely followed because of the risk for multifocality/recurrence. (ProQuest: ... denotes formulae/symbols omitted.)