Lineage tracing of soma-to-primordial germ cell-like conversion in human tumor cell line

Identifying the origin of tumor-initiating ability is of great interest because it provides potential targets for therapy. It has been documented that early primordial germ cells (PGCs) possess inherent tumor-initiating ability, while we previously reported that soma-to-PGC-like conversion (SPLC) is activated and represents a key step in acquiring tumor-initiating ability in mouse breast tumor cells. Here, we demonstrated the activation of SPLC in the human hepatic tumor cell line HL7721. Tumor cells at sequential developmental stages spontaneously appeared in HL7721 cultures, progressing from somatic tumor cells through intermediate stages to the PGC-like stage and late germ cell-like stage, suggesting the activation of SPLC in human tumor cells. Knockdown of either PGC specification inducers (ACVR1, SMAD5, PRDM1, or SOX17) or PGC fate-maintaining genes (NANOG or DDX4) suppressed both SPLC and tumor initiation. Collectively, our findings reveal that SPLC can indeed be activated in human tumor cells, that it is one of the key ways to acquire tumor-initiating ability, and that it is regulated by the signaling pathways involved in human PGC specification and development. This indicates that the ancient mechanism by which somatic cells return to PGC-like cells in some lower organisms could be reactivated in human tumor progression, endowing them with tumor-initiating ability. Our findings provide strong evidence for Old's concept that reacquiring the PGC-like fate in somatic cells serves as a driving force for tumor malignant progression and offer novel paradigms for the targeted therapy of human tumors.