Induction of SOX17 with stimulation of WNT, TGF-beta and FGF signaling drives embryonal carcinomas into the yolk-sac tumor lineage resulting in increased cisplatin resistance

Relapsing germ cell tumor (GCT) patients often harbour components of the aggressive subtype yolk-sac tumor (YST), suggesting that YST formation is an escape mechanism under therapy. Nevertheless, the molecular mechanisms inducing YST development from its stem cell-like precursor embryonal carcinoma (EC) are largely unexplored.
We demonstrated that induction of the transcription factor SOX17 together with stimulation of WNT, TGF-beta/Activin and FGF signalling drives EC cells to into the YST lineage. Single-cell-RNA-sequencing revealed that this cell fate switch was accompanied by upregulation of the typical YST factors AFP, ANKRD1, APOA1, CST1, FOXA2, GATA6 and GPC3 and microRNAs, while pluripotency-related genes NANOG, POU5F1, andSOX2 were downregulated. Chromatin-immunoprecipitation followed by sequencing analysis revealed that SOX17 may act in concert with FOXA2 and GATA factors to initiate YST formation. Xenografting of the YST-like cells into nude mice led to growth of mixed GCT with YST components, confirming that these cells are able to form a YST in vivo. Moreover, expression of cisplatin resistance factors was induced in a subpopulation of YST-like cells, suggesting that formation of a YST is accompanied by acquisition of cisplatin resistance. Indeed, the YST-like cells presented as less sensitive towards cisplatin than their parental cells.
Our study deciphered the molecular mechanisms forcing EC to differentiate into the YST lineage, which is accompanied by acquisition of cisplatin resistance, confirming that YST formation is an escape mechanism for GCT under therapy. Thus, GCT patients should be screened for YST elements under therapy to identify patients in risk of developing therapy resistance.