Next Article in Journal
Interplay Between LOX Enzymes and Integrins in the Tumor Microenvironment
Previous Article in Journal
Acute Skin Damage and Late Radiation-Induced Fibrosis and Inflammation in Murine Ears after High-Dose Irradiation
Article

TCam-2 Cells Deficient for SOX2 and FOXA2 Are Blocked in Differentiation and Maintain a Seminoma-Like Cell Fate In Vivo

1
Department of Urology, Urological Research Lab, Translational Urooncology, University Hospital Düsseldorf, 40225 Düsseldorf, Germany
2
Department of Developmental Pathology, Institute of Pathology, Bonn University Medical School, 53127 Bonn, Germany
*
Author to whom correspondence should be addressed.
These authors share equal contribution.
Cancers 2019, 11(5), 728; https://doi.org/10.3390/cancers11050728
Received: 8 May 2019 / Revised: 22 May 2019 / Accepted: 23 May 2019 / Published: 25 May 2019
Testicular germ cell tumors (GCTs) are very common in young men and can be stratified into seminomas and non-seminomas. While seminomas share a similar gene expression and epigenetic profile with primordial germ cells, the stem cell population of the non-seminomas, the embryonal carcinoma (EC), resembles malignant embryonic stem cells. Thus, ECs are able to differentiate into cells of all three germ layers (teratomas) and even extra-embryonic-tissue-like cells (yolk-sac tumor, choriocarcinoma). In the last years, we demonstrated that the cellular microenvironment considerably influences the plasticity of seminomas (TCam-2 cells). Upon a microenvironment-triggered inhibition of the BMP signaling pathway in vivo (murine flank or brain), seminomatous TCam-2 cells reprogram to an EC-like cell fate. We identified SOX2 as a key factor activated upon BMP inhibition mediating the reprogramming process by regulating pluripotency, reprogramming and epigenetic factors. Indeed, CRISPR/Cas9 SOX2-deleted TCam-2 cells were able to maintain a seminoma-cell fate in vivo for about six weeks, but after six weeks in vivo still small sub-populations initiated differentiation. Closer analyses of these differentiated clusters suggested that the pioneer factor FOXA2 might be the driving force behind this induction of differentiation, since many FOXA2 interacting genes and differentiation factors like AFP, EOMES, CDX1, ALB, HAND1, DKK, DLK1, MSX1 and PITX2 were upregulated. In this study, we generated TCam-2 cells double-deficient for SOX2 and FOXA2 using the CRISPR/Cas9 technique and xenografted those cells into the flank of nude mice. Upon loss of SOX2 and FOXA2, TCam-2 maintained a seminoma cell fate for at least twelve weeks, demonstrating that both factors are key players in the reprogramming to an EC-like cell fate. Therefore, our study adds an important piece to the puzzle of GCT development and plasticity, providing interesting insights in what can be expected in a patient, when GCT cells are confronted with different microenvironments. View Full-Text
Keywords: germ cell tumors; seminoma; embryonal carcinoma; reprogramming; microenvironment; SOX2; FOXA2 germ cell tumors; seminoma; embryonal carcinoma; reprogramming; microenvironment; SOX2; FOXA2
Show Figures

Figure 1

MDPI and ACS Style

Nettersheim, D.; Vadder, S.; Jostes, S.; Heimsoeth, A.; Schorle, H. TCam-2 Cells Deficient for SOX2 and FOXA2 Are Blocked in Differentiation and Maintain a Seminoma-Like Cell Fate In Vivo. Cancers 2019, 11, 728. https://doi.org/10.3390/cancers11050728

AMA Style

Nettersheim D, Vadder S, Jostes S, Heimsoeth A, Schorle H. TCam-2 Cells Deficient for SOX2 and FOXA2 Are Blocked in Differentiation and Maintain a Seminoma-Like Cell Fate In Vivo. Cancers. 2019; 11(5):728. https://doi.org/10.3390/cancers11050728

Chicago/Turabian Style

Nettersheim, Daniel, Saskia Vadder, Sina Jostes, Alena Heimsoeth, and Hubert Schorle. 2019. "TCam-2 Cells Deficient for SOX2 and FOXA2 Are Blocked in Differentiation and Maintain a Seminoma-Like Cell Fate In Vivo" Cancers 11, no. 5: 728. https://doi.org/10.3390/cancers11050728

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop