Mechanisms of Smarcb1depending PGC transformation

• Applicant: Professor Dr. Kornelius Kerl
• Subject Area: Hematology, Oncology ; Pediatric and Adolescent Medicine ; Cell Biology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 505327467

Primordial germ cells (PGC) are the cell of origin of distinct germ cell tumors, but also of a defined molecular subgroup of rhabdoid tumors (RT): intracranial, as well as extracranial rhabdoid tumors of the MYC subgroup (RT-MYC) originate from PGCs. RT are aggressively growing tumors, which are associated with a poor prognosis and which occur with a peak incidence until the third year of age. The RT characterizing mutation in the SMARCB1 gene results in an epigenetic imbalance in these tumor cells, which is followed by the deregulation of multiple downstream signaling pathways. On the other hand mechanisms are unknown, which result in the transformation of PGC after Smarcb1 loss and which are thereby early mechanisms of RT development. To delineate those mechanisms of RT transformation in a time dependend manner in this project, in preliminary work the applicant has identified PGCs as the cellular origin of RT-MYC. These preliminary results are the basis to examine mechanisms how SMARCB1 loss impacts cellular functions, the transcriptome and epigenome of PGCs. Therefore 2D and 3D in vitro models are used to explore the impact of SMARCB1 loss on PGCs cellular function as the regulation of cell proliferation, cell cycle, apoptosis and migration. To unravel early changes after SMARCB1 loss on the transcriptome and epigenome, SMARCB1 loss is induced in 2D and 3 D in vitro models, as well as in mouse xenograft models and changes are detected by using single cell RNA sequencing, DNA methylation arrays and ChIP sequencing at distinct time points of transformation. The results of this project will not only give insights into mechanisms of RT development, but will also unravel mechanisms how PGCs transform and how cellular functions (as for example cell migration) are regulated in PGC by epigenetic mechanisms.

• DFG Programme: Research Grants