TY - JOUR
T1 - Role of BRAFV600E in the first preclinical model of multifocal infiltrating myopericytoma development and microenvironment
AU - Sadow, Peter M.
AU - Priolo, Carmen
AU - Nanni, Simona
AU - Karreth, Florian A.
AU - Duquette, Mark
AU - Martinelli, Roberta
AU - Husain, Amjad
AU - Clohessy, John
AU - Kutzner, Heinz
AU - Mentzel, Thomas
AU - Carman, Christopher V.
AU - Farsetti, Antonella
AU - Henske, Elizabeth Petri
AU - Palescandolo, Emanuele
AU - Macconaill, Laura E.
AU - Chung, Seum
AU - Fadda, Guido
AU - Lombardi, Celestino Pio
AU - De Angelis, Antonina M.
AU - Durante, Oreste
AU - Parker, John A.
AU - Pontecorvi, Alfredo
AU - Dvorak, Harold F.
AU - Fletcher, Christopher
AU - Pandolfi, Pier Paolo
AU - Lawler, Jack
AU - Nucera, Carmelo
PY - 2014/8/1
Y1 - 2014/8/1
N2 - 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 BRAFWT/V600E; 33.3% (1 of 3 samples) of BRAFWT/V600E-MPCs were multifocal/infiltrative/recurrent. Patient-MPC and primary MPC cells harbored BRAFWT/V600E, were clonal and expressed pericytic-differentiation biomarkers crucial for its microenvironment. BRAFWT/V600Epositive thyroid MPC primary cells triggered in vitro (8.8-fold increase) and in vivo (3.6-fold increase) angiogenesis. Anti-BRAFV600E 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 BRAFWT-pericytes. Vemurafenib also inhibited (∼3-fold decrease) cell viability in vitro and in BRAFWT/V600E-positive thyroid MPC patient-derived xenograft (PDX) mice (n = 5 mice per group). We established the first BRAFWT/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 BRAFWT/V600EMPC patients. Patients with BRAFWT/V600E-MPC should be closely followed because of the risk for multifocality/recurrence.
AB - 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 BRAFWT/V600E; 33.3% (1 of 3 samples) of BRAFWT/V600E-MPCs were multifocal/infiltrative/recurrent. Patient-MPC and primary MPC cells harbored BRAFWT/V600E, were clonal and expressed pericytic-differentiation biomarkers crucial for its microenvironment. BRAFWT/V600Epositive thyroid MPC primary cells triggered in vitro (8.8-fold increase) and in vivo (3.6-fold increase) angiogenesis. Anti-BRAFV600E 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 BRAFWT-pericytes. Vemurafenib also inhibited (∼3-fold decrease) cell viability in vitro and in BRAFWT/V600E-positive thyroid MPC patient-derived xenograft (PDX) mice (n = 5 mice per group). We established the first BRAFWT/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 BRAFWT/V600EMPC patients. Patients with BRAFWT/V600E-MPC should be closely followed because of the risk for multifocality/recurrence.
UR - http://www.scopus.com/inward/record.url?scp=84930687027&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84930687027&partnerID=8YFLogxK
U2 - 10.1093/jnci/dju182
DO - 10.1093/jnci/dju182
M3 - Article
VL - 106
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
SN - 0027-8874
IS - 8
M1 - dju182
ER -