Division of Biomedical Research, Medical University Graz, Graz, Austria.
Laboratorio di Ricerca Traslazionale Arcispedale S. Maria Nuova - IRCCS, Reggio Emilia, Italy.
Sci Rep. 2017 May 18;7(1):2098. doi: 10.1038/s41598-017-02197-y.
NRAS mutation in melanoma has been associated with aggressive tumor biology and poor prognosis. Although targeted therapy has been tested for NRAS mutated melanoma, response rates still appear much weaker, than in BRAF mutated melanoma. While plenty of cell lines exist, however, only few melanogenic cell lines retain their in vivo characteristics. In this work we present an intensively pigmented and well-characterized cell line derived from a highly aggressive NRAS mutated cutaneous melanoma, named MUG-Mel2. We present the clinical course, unique morphology, angiogenic properties, growth characteristics using in vivo experiments and 3D cell culture, and results of the exome gene sequencing of an intensively pigmented melanogenic cell line MUG-Mel2, derived from a cutaneous metastasis of an aggressive NRAS p. Q61R mutated melanoma. Amongst several genetic alterations, mutations in GRIN2A, CREBP, PIK3C2G, ATM, and ATR were present. These mutations, known to reinforce DNA repair problems in melanoma, might serve as potential treatment targets. The aggressive and fast growing behavior in animal models and the obtained phenotype in 3D culture reveal a perfect model for research in the field of NRAS mutated melanoma.
NRAS 突变与黑色素瘤侵袭性肿瘤生物学和不良预后相关。虽然已经针对 NRAS 突变黑色素瘤进行了靶向治疗,但反应率似乎仍然比 BRAF 突变黑色素瘤弱得多。虽然存在大量的细胞系,但只有少数黑素生成细胞系保留了体内特征。在这项工作中,我们展示了一种源自高度侵袭性 NRAS 突变皮肤黑色素瘤的高度色素沉着且特征良好的细胞系,命名为 MUG-Mel2。我们介绍了临床过程、独特的形态、血管生成特性、体内实验和 3D 细胞培养中的生长特征,以及源自侵袭性 NRAS p.Q61R 突变黑色素瘤皮肤转移的高度色素沉着黑素生成细胞系 MUG-Mel2 的外显子组基因测序结果。存在几种遗传改变,包括 GRIN2A、CREBP、PIK3C2G、ATM 和 ATR 的突变。这些突变已知会加重黑色素瘤中的 DNA 修复问题,可能成为潜在的治疗靶点。在动物模型中的侵袭性和快速生长行为以及在 3D 培养中获得的表型揭示了研究 NRAS 突变黑色素瘤领域的理想模型。