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

Summary Identifying the origin of tumor-initiating ability is critical for targeted therapies. While early primordial germ cells (PGCs) inherently possess this ability, our previous study indicated that soma-to-PGC-like conversion (SPLC) facilitates its acquisition in mouse breast tumor cells. This study reports evidence of SPLC activation in the human hepatic tumor cell line HL7721, where tumor cells spontaneously exhibit sequential developmental stages, progressing from somatic tumor cells through intermediate stages to PGC-like and late germ cell-like stages. Knocking out PGC specification inducers (ACVR1, SMAD5, PRDM1, or SOX17) or fate-maintaining genes (NANOG or DDX4) suppressed both SPLC and tumor initiation. Collectively, our findings suggest that SPLC might be activated in human tumor cells, serving as a potential pathway for gaining tumor-initiating ability that involves human PGC-related pathways. These results demonstrate that the acquisition of PGC-like fate in somatic cells drives tumor malignant progression, providing a potential paradigm for targeted cancer therapy.