SOX2 is essential for in vivo reprogramming of seminoma-like TCam-2 cells to an embryonal carcinoma-like fate.
SOX2 is essential for in vivo reprogramming of seminoma-like TCam-2 cells to an embryonal carcinoma-like fate.
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DOI：
10.18632/oncotarget.9903
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发表时间：
2016-07-26
期刊：
影响因子：
--
通讯作者：
Schorle H
中科院分区：
文献类型：
--
作者：
Nettersheim D;Heimsoeth A;Jostes S;Schneider S;Fellermeyer M;Hofmann A;Schorle H
II型生殖细胞癌（GCC）分为精原细胞瘤，与原始生殖细胞和胚胎癌（EC）高度相似，通常被描述为胚胎干细胞的恶性对应物。之前，我们证明了 GCC 的发展是一个高度可塑的过程，并且受到微环境的强烈影响。原位移植到睾丸可促进精原细胞瘤样细胞系 TCam-2 的精原细胞生长，而异位异种移植到侧腹则会启动重编程为 EC 样命运。在此重编程过程中，BMP 信号传导受到抑制，导致 NODAL 信号传导的诱导、多能性因子的上调和精原细胞瘤标志物（如 SOX17）的下调。多能因子和 EC 标记 SOX2 被强烈诱导。在这里，我们讨论了 SOX2 在这种重编程中的分子作用。使用 CRISPR/Cas9 介导的基因组编辑，我们建立了 SOX2 缺陷的 TCam-2 细胞。将 SOX2 缺陷细胞异种移植到裸鼠胁腹后，可维持类似精原细胞瘤的命运，这由 OCT3/4、SOX17、TFAP2C、PRDM1 和 PRAME 的组织学和表达表明。在 SOX2 缺陷细胞中，BMP 信号传导受到抑制，但 NODAL 信号传导未激活。因此，SOX2 似乎位于 BMP 信号传导的下游，但位于 NODAL 激活的上游。因此，SOX2 是精原细胞瘤获得类似 EC 细胞命运的重要因素。鉴定出一小群分化细胞，类似于混合非精原细胞瘤。对这些细胞的分析揭示了多能性和精原细胞瘤标记物 OCT3/4、SOX17、PRDM1 和 TFAP2C 的下调。相反，先锋因子FOXA2及其靶基因表达上调，表明FOXA2可能在诱导非精原细胞分化中发挥重要作用。
Type II germ cell cancers (GCC) are divided into seminomas, which are highly similar to primordial germ cells and embryonal carcinomas (EC), often described as malignant counterparts to embryonic stem cells. Previously, we demonstrated that the development of GCCs is a highly plastic process and strongly influenced by the microenvironment. While orthotopic transplantation into the testis promotes seminomatous growth of the seminoma-like cell line TCam-2, ectopic xenotransplantation into the flank initiates reprogramming into an EC-like fate. During this reprogramming, BMP signaling is inhibited, leading to induction of NODAL signaling, upregulation of pluripotency factors and downregulation of seminoma markers, like SOX17. The pluripotency factor and EC-marker SOX2 is strongly induced. Here, we adressed the molecular role of SOX2 in this reprogramming. Using CRISPR/Cas9-mediated genome-editing, we established SOX2-deficient TCam-2 cells. Xenografting of SOX2-deficient cells into the flank of nude mice resulted in maintenance of a seminoma-like fate, indicated by the histology and expression of OCT3/4, SOX17, TFAP2C, PRDM1 and PRAME. In SOX2-deficient cells, BMP signaling is inhibited, but NODAL signaling is not activated. Thus, SOX2 appears to be downstream of BMP signaling but upstream of NODAL activation. So, SOX2 is an essential factor in acquiring an EC-like cell fate from seminomas. A small population of differentiated cells was identified resembling a mixed non-seminoma. Analyses of these cells revealed downregulation of the pluripotency and seminoma markers OCT3/4, SOX17, PRDM1 and TFAP2C. In contrast, the pioneer factor FOXA2 and its target genes were upregulated, suggesting that FOXA2 might play an important role in induction of non-seminomatous differentiation.
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影响因子：
4
作者：
Kaestner, Klaus H.
通讯作者：
Kaestner, Klaus H.
影响因子：
3.7
作者：
Kerschner, Jenny L.;Gosalia, Nehal;Harris, Ann
通讯作者：
Harris, Ann
影响因子：
--
作者：
Eckert, Dawid;Biermann, Katharina;Nettersheim, Daniel;Gillis, Ad J. M.;Steger, Klaus;Jaeck, Hans-Martin;Mueller, Annette M.;Looijenga, Leendert H. J.;Schorle, Hubert
通讯作者：
Schorle, Hubert
DOI：
10.1073/pnas.1505569112
发表时间：
2015-05-05
影响因子：
11.1
作者：
Cattoglio, Claudia;Zhang, Elisa T.;Tjian, Robert
通讯作者：
Tjian, Robert
影响因子：
21.3
作者：
Ancelin, Katia;Lange, Ulrike C.;Surani, M. Azim
通讯作者：
Surani, M. Azim