Role of BRAF^V600E in the first preclinical model of multifocal infiltrating myopericytoma development and microenvironment

Myopericytoma (MPC) is a rare tumor with perivascular proliferation of pluripotent stemcell- 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^WT/V600E; 33.3% (1 of 3 samples) of BRAF^WT/V600E-MPCs were multifocal/infiltrative/recurrent. Patient-MPC and primary MPC cells harbored BRAF^WT/V600E, were clonal and expressed pericytic-differentiation biomarkers crucial for its microenvironment. BRAF^WT/V600Epositive thyroid MPC primary cells triggered in vitro (8.8-fold increase) and in vivo (3.6-fold increase) angiogenesis. Anti-BRAF^V600E 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 noncoding RNA (LincRNA) expression, with no effects in BRAF^WT-pericytes. Vemurafenib also inhibited (∼3-fold decrease) cell viability in vitro and in BRAF^WT/V600E-positive thyroid MPC patient-derived xenograft (PDX) mice (n = 5 mice per group). We established the first BRAF^WT/V600E-dependent thyroid MPC cell culture. Our findings identify BRAFWT/V600E as a novel genetic aberration in MPC pathogenesis and MPC-associated biomarkers and imply that anti-BRAFV600E agents may be useful adjuvant therapy in BRAF^WT/V600EMPC patients. Patients with BRAF^WT/V600E-MPC should be closely followed because of the risk for multifocality/recurrence.