Role of BRAFV600E in the first preclinical model of multifocal infiltrating myopericytoma development and microenvironment

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 DuranteJohn A. Parker, Alfredo Pontecorvi, Harold F. Dvorak, Christopher Fletcher, Pier Paolo Pandolfi, Jack Lawler, Carmelo Nucera

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Abstract

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.

Original languageEnglish
Article numberdju182
JournalJournal of the National Cancer Institute
Volume106
Issue number8
DOIs
Publication statusPublished - Aug 1 2014

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Sadow, P. M., Priolo, C., Nanni, S., Karreth, F. A., Duquette, M., Martinelli, R., Husain, A., Clohessy, J., Kutzner, H., Mentzel, T., Carman, C. V., Farsetti, A., Henske, E. P., Palescandolo, E., Macconaill, L. E., Chung, S., Fadda, G., Lombardi, C. P., De Angelis, A. M., ... Nucera, C. (2014). Role of BRAFV600E in the first preclinical model of multifocal infiltrating myopericytoma development and microenvironment. Journal of the National Cancer Institute, 106(8), [dju182]. https://doi.org/10.1093/jnci/dju182