Developmental Origins of Pediatric Cancer

Tumor Initiation
In SHH-medulloblastoma, nearly 40% of patients have mutations in known hereditary predisposition genes. Recently, the gene ELP1 was identified as the most frequently mutated hereditary predisposition gene. ELP1 encodes the scaffolding member of the Elongator complex, which is involved in modifying tRNAs for efficient translation; how mutations in ELP1 predispose patients to tumors is unknown. Therefore, we are investigating the effect of ELP1 heterozygous mutations on GNP biology using mouse and iPSC-based cerebellar organoid models. Our future work builds upon the models we have established studying ELP1 to understand other types of hereditary predisposition and the role of germline mutations in tumor initiation. See Schloo and Kutscher 2023 for discussion of iPSC-based models of pediatric brain cancer.

Developmental Cell Death
Programmed cell death is a vital process in multicellular organism development. Although apoptosis is assumed to be the primary cell death mechanism during development, some mice lacking intrinsic apoptosis survive to adulthood, challenging this assumption. We hypothesize that the mechanism of developmental cell death called linker cell-type death (LCD), identified so far only in the nematode C. elegans (Kutscher et al 2018), exists in mammals, and is operating in parallel to apoptosis to shape early mammalian development. An H3K4 methyltransferase complex and an E3 ubiquitin ligase are implicated in LCD in C. elegans, and their human homologs are mutated in pediatric brain cancer. These shared underlie the hypothesis that perhaps mutations which hinder proper developmental non-apoptotic cell death may be in part responsible for developmental brain cancer. After identifying the genes required for normal LCD in mice, we will investigate whether these genes also have a functional role in pediatric medulloblastoma formation.