Oncotarget

Research Papers:

SOX2 is essential for in vivo reprogramming of seminoma-like TCam-2 cells to an embryonal carcinoma-like fate

Daniel Nettersheim, Alena Heimsoeth, Sina Jostes, Simon Schneider, Martin Fellermeyer, Andrea Hofmann and Hubert Schorle _

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Oncotarget. 2016; 7:47095-47110. https://doi.org/10.18632/oncotarget.9903

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Abstract

Daniel Nettersheim1, Alena Heimsoeth1, Sina Jostes1, Simon Schneider1, Martin Fellermeyer1, Andrea Hofmann2, Hubert Schorle1

1Institute of Pathology, Department of Developmental Pathology, University of Bonn Medical School, Bonn, Germany

2Institute of Human Genetics, University of Bonn Medical School, Bonn, Germany

Correspondence to:

Hubert Schorle, email: [email protected]

Keywords: TCam-2, seminoma, embryonal carcinoma, reprogramming, SOX2/SOX17

Received: March 22, 2016     Accepted: May 19, 2016     Published: June 07, 2016

ABSTRACT

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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