Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
PLoS One. 2009 Dec 24;4(12):e8461. doi: 10.1371/journal.pone.0008461.
We are investigating the molecular basis of melanoma by defining genomic characteristics that correlate with tumour phenotype in a novel panel of metastatic melanoma cell lines. The aim of this study is to identify new prognostic markers and therapeutic targets that might aid clinical cancer diagnosis and management.
Global transcript profiling identified a signature featuring decreased expression of developmental and lineage specification genes including MITF, EDNRB, DCT, and TYR, and increased expression of genes involved in interaction with the extracellular environment, such as PLAUR, VCAN, and HIF1a. Migration assays showed that the gene signature correlated with the invasive potential of the cell lines, and external validation by using publicly available data indicated that tumours with the invasive gene signature were less melanocytic and may be more aggressive. The invasion signature could be detected in both primary and metastatic tumours suggesting that gene expression conferring increased invasive potential in melanoma may occur independently of tumour stage.
Our data supports the hypothesis that differential developmental gene expression may drive invasive potential in metastatic melanoma, and that melanoma heterogeneity may be explained by the differing capacity of melanoma cells to both withstand decreased expression of lineage specification genes and to respond to the tumour microenvironment. The invasion signature may provide new possibilities for predicting which primary tumours are more likely to metastasize, and which metastatic tumours might show a more aggressive clinical course.
我们通过定义与新型转移性黑素瘤细胞系肿瘤表型相关的基因组特征，来研究黑素瘤的分子基础。本研究旨在鉴定新的预后标志物和治疗靶点，以辅助临床癌症诊断和治疗。
全局转录谱分析确定了一个特征，即发育和谱系特化基因的表达降低，包括 MITF、EDNRB、DCT 和 TYR，而参与与细胞外环境相互作用的基因表达增加，如 PLAUR、VCAN 和 HIF1a。迁移实验表明，基因特征与细胞系的侵袭潜能相关，并且使用公开可用数据进行的外部验证表明，具有侵袭性基因特征的肿瘤黑素细胞较少，可能更具侵袭性。侵袭性基因特征可在原发性和转移性肿瘤中检测到，这表明赋予黑素瘤侵袭潜能的基因表达可能独立于肿瘤阶段发生。
我们的数据支持这样一种假设，即差异发育基因表达可能驱动转移性黑素瘤的侵袭潜能，而黑素瘤异质性可以通过黑素瘤细胞的不同能力来解释，即黑素瘤细胞能够耐受谱系特化基因表达的降低，并对肿瘤微环境做出反应。侵袭性基因特征可能为预测哪些原发性肿瘤更有可能转移以及哪些转移性肿瘤可能表现出更具侵袭性的临床病程提供新的可能性。
