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

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalJournal of the National Cancer Institute
Volume106
Issue number8
Publication statusPublished - 2014

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Thyroid Gland
Pericytes
Biomarkers
Extracellular Matrix
Long Noncoding RNA
Pluripotent Stem Cells
Heterografts
Cell Survival
Down-Regulation
Cell Culture Techniques
Recurrence
Skin
Therapeutics
Neoplasms
In Vitro Techniques
PLX4032

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Sadow, P. M., Priolo, C., Nanni, S., Karreth, F. A., Duquette, M., Martinelli, R., ... 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).

Role of BRAFV600E in the first preclinical model of multifocal infiltrating myopericytoma development and microenvironment. / 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; Parker, John A.; Pontecorvi, Alfredo; Dvorak, Harold F.; Fletcher, Christopher; Pandolfi, Pier Paolo; Lawler, Jack; Nucera, Carmelo.

In: Journal of the National Cancer Institute, Vol. 106, No. 8, 2014.

Research output: Contribution to journalArticle

Sadow, PM, Priolo, C, Nanni, S, Karreth, FA, Duquette, M, Martinelli, R, Husain, A, Clohessy, J, Kutzner, H, Mentzel, T, Carman, CV, Farsetti, A, Henske, EP, Palescandolo, E, Macconaill, LE, Chung, S, Fadda, G, Lombardi, CP, De Angelis, AM, Durante, O, Parker, JA, Pontecorvi, A, Dvorak, HF, Fletcher, C, Pandolfi, PP, Lawler, J & Nucera, C 2014, 'Role of BRAFV600E in the first preclinical model of multifocal infiltrating myopericytoma development and microenvironment.', Journal of the National Cancer Institute, vol. 106, no. 8.
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 ; Parker, John A. ; Pontecorvi, Alfredo ; Dvorak, Harold F. ; Fletcher, Christopher ; Pandolfi, Pier Paolo ; Lawler, Jack ; Nucera, Carmelo. / Role of BRAFV600E in the first preclinical model of multifocal infiltrating myopericytoma development and microenvironment. In: Journal of the National Cancer Institute. 2014 ; Vol. 106, No. 8.
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title = "Role of BRAFV600E in the first preclinical model of multifocal infiltrating myopericytoma development and microenvironment.",
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.",
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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

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