Primordial germ cells identified as one potential cell of origin of MYC rhabdoid tumors

Rhabdoid tumors (RT) are rare and highly aggressive pediatric neoplasms. Their epigenetically-driven intertumoral heterogeneity is well described; however, the cellular origin of RT remains an enigma. Here, we established and characterized different genetically engineered mouse models driven under the control of distinct promoters and being active in early progenitor cell types with diverse embryonic onsets. From all models only Sox2-positive progenitor cells give rise to murine RT. Using single-cell analyses, we identified distinct cells of origin for the SHH and MYC subgroups of RT, rooting in early stages of embryogenesis. Intra- and extracranial MYC tumors harbor common genetic programs and potentially originate from fetal primordial germ cells (PGCs). Using PGC specific Smarcb1 knockout mouse models we validated that MYC RT originate from these progenitor cells. We uncovered an epigenetic imbalance in MYC tumors compared to PGCs being sustained by epigenetically-driven subpopulations. Importantly, treatments with the DNA demethylating agent decitabine successfully impaired tumor growth in vitro and in vivo. We utilized gene expression profiling (Affymetrix GeneChip Mouse Gene 2.0 ST Array) of tumors derived from the Sox2-cre, Sox2-creERT2 and Rosa26-creERT2 Smarcb1 knockout models generating SHH and MYC RT. For this, we crossed the Smarcb1 fl/fl strain with the mouse line harboring the Cre or CreERT2 coding region under the control of ubiquitous (Rosa26) or cell specific (Sox2) promoter. When required (CreERT2), pregnant females were induced with a single intraperitoneal dose (50 mg/kg) of Tamoxifen at 6.5 days post-coitum (post-coital plug observation was considered as day 0.5). All mice were intensively monitored until neurological symptoms or macroscopical abnormalities indicating tumor growth were observed. Total RNA from the tumor sample was extracted for a total number of 41 samples, processed into 3 separate batches.