Developmental transcription factors in Drosha-driven cancer

PROJECT SUMMARY/ABSTRACT Pineoblastoma is one of a family of childhood cancers that can arise through mutations in microRNA processing genes DROSHA and DICER1. It is unknown whether these tumors develop through shared or distinct oncogenic pathways, and there are no ways to therapeutically target such mutations. To understand how these mutations cause cancer, we developed a mouse model of pineoblastoma by ablating Drosha or Dicer1 in the developing pineal gland. These mice develop tumors that resemble human pineoblastoma. They are highly proliferative; they exhibit an expression signature of the embryonic pineal gland; and they overexpress microRNA target genes. Among the microRNA target genes overexpressed in these tumors is a set of developmental transcription factors, including Onecut2. Furthermore, the binding sequences recognized by these transcription factors is enriched in regions of open chromatin in these pineal tumors. In this project, we will investigate the role of Onecut2 in the developing pineal gland and in pineal tumor development. In Aim 1, we test whether Onecut2 is necessary for tumor development. In Aim 2, we investigate how Onecut2 interacts with other neurodevelopmental transcription factors. In Aim 3, we explore whether ONECUT2 is required in patient-derived models of pineoblastoma. If successful, this project would demonstrate that mutations in DROSHA or DICER1 can arrest differentiation through developmental transcription factors and that impairing the activity of these transcription factors could be a future therapeutic strategy.