UCSF

Sacrococcygeal teratomas (SCTs) are the most common neonatal tumors, yet their developmental origins, molecular mechanisms, and female-sex bias remain poorly understood. This thesis integrates spatial transcriptomics, single-cell RNA sequencing, and experimental models to investigate SCT biology and its hypothesized origins from primordial germ cells (PGCs). We first examined female primate ovarian reserve establishment, showing that rhesus macaque primordial follicles arise from two pre-granulosa cell subtypes, with PG2 cells predominating and supporting early hormone production before birth. We then generated a cellular atlas of SCTs, revealing epithelia-rich and epithelia-poor subtypes, marked inter-tumor heterogeneity, and evidence that X-chromosome inactivation failure in female tumors may contribute to observed sex biases. Finally, using iPSC-derived PGC-like cells, we modeled germ cell reprogramming to pluripotency, identifying transcriptional, metabolic, and epigenetic remodeling events, including DNMT3B-mediated DNA methylation. We also initiated development of a dual SOX2–SOX17 reporter system to follow this process and explored hindgut organoid co-cultures and fetal mouse injections as potential platforms to study environmental influences on germ cell fate. Together, these studies provide insights into fetal ovarian development, highlight sources of heterogeneity in SCTs, and suggest possible mechanisms by which germ cell reprogramming could contribute to tumor origins.