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- Title
Role of BRAFV600E in the First Preclinical Model of Multifocal Infiltrating Myopericytoma Development and Microenvironment.
- Authors
Sadow, Peter M.; Priolo, Carmen; Nanni, Simona; Karreth, Florian A.; Duquette, Mark; Martinelli, Roberta; Husain, Amjad; Clohessy, John; Kutzner, Heinz; Mentzel, Thomas; Carman, Christopher V.; Farsetti, Antonella; Henske, Elizabeth Petri; Palescandolo, Emanuele; Macconaill, Laura E.; Chung, Seum; Fadda, Guido; Lombardi, Celestino Pio; De Angelis, Antonina M.; Durante, Oreste
- 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 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/V600E-positive 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 non-coding 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/V600E-MPC patients. Patients with BRAFWT/V600E-MPC should be closely followed because of the risk for multifocality/recurrence.
- Subjects
BRAF genes; TUMOR growth; ETIOLOGY of cancer; ETIOLOGY of diseases; CANCER research
- Publication
JNCI: Journal of the National Cancer Institute, 2014, Vol 106, Issue 8, p1
- ISSN
0027-8874
- Publication type
Article
- DOI
10.1093/jnci/dju182