Investigating the role of apoptosis-resistance and the tumor environment on development and maintenance of sacrococcygeal teratomas

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PROJECT SUMMARY/ABSTRACT Sacrococcygeal teratomas (SCTs) are the most common tumor in newborns, have significant perinatal morbidity and mortality, a 35% rate of recurrence, and lack good biomarkers to predict recurrence risk. SCTs are believed to originate from apoptosis-resistant embryonic gamete-precursors known as primordial germ cells (PGCs). In mice, PGCs can revert to pluripotent cells called embryonic germ cells (EGCs) when exposed to a specific cocktail of growth factors, however, establishing an in vitro model of human EGCs has been technically and ethically challenging. The proposed Research Training Plan will leverage human induced pluripotent stem cell derived PGC-like cells (PGC-LCs) and EGC-like cells (EGC-LCs), single cell multi-omic technologies, and an innovative mouse embryonic injection model to study the process by which PGCs lead to teratoma formation. The central hypothesis is that SCTs arise from apoptosis-resistant ectopic PGCs that have been reverted to a pluripotent state resembling PGC to EGC reversion, and the most aggressive SCTs have tumor environment interactions that maintain these pluripotent cells. In Aim 1, the trainee, MD PhD candidate Ernesto Rojas, will define the chromatin and transcriptional landscape of PGC-LC to EGC-LC reversion with and without apoptosis- resistance. Then, using the in utero injection model he developed, he will characterize the differences in tumorigenic potential between PGC-LC and EGC-LCs, with and without inhibition of apoptosis. In Aim 2, the candidate will identify and modulate pathways maintaining pluripotency in SCTs. He will use single-cell transcriptomics to identify pathways that may modulate the tumorigenicity of EGC-LCs, and will functionally validate these pathways using the PGC-LC to EGC-LC reversion model and the transplant model to find those pathways that improve maintenance of EGC-LCs. The results of Aim 1 will provide the first roadmap of the changes in chromatin and gene expression that occur during reversion from germline to pluripotency to teratoma. The results of Aim 2 will provide potential biomarkers and targetable pathways for future clinical use in SCTs. These studies will identify the important developmental trajectories that occur with reversion from PGC to pluripotency, improve insight to aid biomarker development for recurrences of PGC-derived tumors, and provide potential targetable pathways to treat the most aggressive tumors. To successfully complete this project, the candidate will work with Drs. Diana Laird (sponsor) and Tippi Mackenzie (co-sponsor). Dr. Laird is a germ cell expert and Dr. Mackenzie is a fetal surgeon. Together with the candidate, they have established a training plan for him to gain new knowledge and skills in developmental and stem cell biology techniques and bioinformatic analyses, as well as clinical training, and professional development. Through the collaborators named in this proposal, the collaborative environment and excellent infrastructure at UCSF, and with the support provided by this fellowship, the candidate will be well equipped to investigate the role of development on early peri-natal health and advance his career as a surgeon-scientist.