Directed Dedifferentiation Using Partial Reprogramming Induces Invasive Phenotype in Melanoma Cells
Directed Dedifferentiation Using Partial Reprogramming Induces Invasive Phenotype in Melanoma Cells
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DOI：
10.1002/stem.2284
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发表时间：
2016-04
期刊：
影响因子：
5.2
通讯作者：
Nathalie Knappe;Daniel Novák;Kasia Weina;Mathias Bernhardt;M. Reith;L. Larribère;M. Hölzel;T. Tüting;C. Gebhardt;V. Umansky;J. Utikal
中科院分区：
文献类型：
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作者：
Nathalie Knappe;Daniel Novák;Kasia Weina;Mathias Bernhardt;M. Reith;L. Larribère;M. Hölzel;T. Tüting;C. Gebhardt;V. Umansky;J. Utikal
以癌症为中心的研究和与核重编程相关的研究的结合变得越来越重要，因为这两个过程（向多能性和恶性转化的重编程）具有共同的基本特征。研究表明，体细胞的不完全重编程会导致恶性转化，表明与 iPSC 生成相关的表观遗传调控可以驱动癌症的发展 [J Mol Cell Biol 2011;341–350;细胞 2012；151：1617–1632；细胞2014；156：663–677]。然而，到目前为止，尚不清楚不完全重编程是否也会影响癌细胞及其功能。在黑色素瘤的背景下，去分化与小鼠研究中的治疗耐药性相关，并且已在黑色素瘤患者中得到记录[Nature 2012;490:412–416;临床癌症研究2014；20：2498–2499]。因此，我们试图利用黑色素瘤细胞的不完全重编程来研究定向去分化。使用小鼠模型，我们研究了部分重编程对黑色素瘤细胞的细胞可塑性的影响。我们首次证明诱导部分重编程会导致黑色素瘤细胞发生可逆表型转换。转基因诱导后第12天，部分重编程的细胞在体外表现出较高的侵袭潜力，在体内则表现出增加的肺部定植。此外，通过对部分重编程细胞的全局基因表达分析，我们发现 SNAI3 是人类黑色素瘤中一种新型的侵袭相关标记物。 SNAI3 表达与原发性黑色素瘤中的肿瘤厚度相关，因此可能具有预后价值。总之，我们表明，研究黑色素瘤细胞重编程过程中的中间状态可以揭示黑色素瘤进展发病机制的新见解。我们建议，对部分重编程的黑色素瘤细胞进行更深入的分析可能有助于识别可驱动黑色素瘤进展的未知信号通路。干细胞 2016；34：832–846
The combination of cancer‐focused studies and research related to nuclear reprogramming has gained increasing importance since both processes—reprogramming towards pluripotency and malignant transformation—share essential features. Studies have revealed that incomplete reprogramming of somatic cells leads to malignant transformation indicating that epigenetic regulation associated with iPSC generation can drive cancer development [J Mol Cell Biol 2011;341–350; Cell 2012;151:1617–1632; Cell 2014;156:663–677]. However, so far it is unclear whether incomplete reprogramming also affects cancer cells and their function. In the context of melanoma, dedifferentiation correlates to therapy resistance in mouse studies and has been documented in melanoma patients [Nature 2012;490:412–416; Clin Cancer Res 2014;20:2498–2499]. Therefore, we sought to investigate directed dedifferentiation using incomplete reprogramming of melanoma cells. Using a murine model we investigated the effects of partial reprogramming on the cellular plasticity of melanoma cells. We demonstrate for the first time that induced partial reprogramming results in a reversible phenotype switch in melanoma cells. Partially reprogrammed cells at day 12 after transgene induction display elevated invasive potential in vitro and increased lung colonization in vivo. Additionally, using global gene expression analysis of partially reprogrammed cells, we identified SNAI3 as a novel invasion‐related marker in human melanoma. SNAI3 expression correlates with tumor thickness in primary melanomas and thus, may be of prognostic value. In summary, we show that investigating intermediate states during the process of reprogramming melanoma cells can reveal novel insights into the pathogenesis of melanoma progression. We propose that deeper analysis of partially reprogrammed melanoma cells may contribute to identification of yet unknown signaling pathways that can drive melanoma progression. Stem Cells 2016;34:832–846