Role of BRAFV600E in the First Preclinical Model of Multifocal Infiltrating Myopericytoma Development and Microenvironment
Year: 2014
Type: article
Abstract: 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(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/V600E)-positive 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 non-coding 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 BRAF(WT/V600E) as a novel genetic aberration in MPC pathogenesis and MPC-associated biomarkers and imply that anti-BRAF(V600E) agents may be useful adjuvant therapy in BRAF(WT/V600E)-MPC patients. Patients with BRAF(WT/V600E)-MPC should be closely followed because of the risk for multifocality/recurrence.
DOI: 10.1093/jnci/dju182
Authors: Peter M. Sadow, Carmen Priolo, Simona Nanni, Florian A. Karreth, Mark Duquette, Roberta Martinelli, Amjad Husain, John Clohessy, Heinz Kutzner, Thomas Mentzel, Christopher V. Carman, Antonella Farsetti, Elizabeth Petri Henske, Emanuele Palescandolo, Laura E. Macconaill, Seum Chung, Guido Fadda, Celestino Pio Lombardi, Antonina M. De Angelis, Oreste Durante, John A. Parker, Alfredo Pontecorvi, Harold F. Dvorak, Christopher Fletcher, Pier Paolo Pandolfi, Jack Lawler, Carmelo Nucera
Institutions: Brigham and Women's Hospital, Beth Israel Deaconess Medical Center, Harvard University, Massachusetts General Hospital, Center for Vascular Biology Research, National Research Council, Università Cattolica del Sacro Cuore, Instituto Nazionale Tumori Regina Elena, National Health Insurance Service Ilsan Hospital, Agostino Gemelli University Polyclinic, Magna Graecia University
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funder: National Cancer Institute
OpenAlex ID: W2010124753