Novel Resilience Genes Required for Cerebellum Development and Medulloblastoma Survival
Medulloblastoma (MB) is a devastating tumor of the cerebellum and is the most common malignant childhood brain tumor. It is a major cause of disease and mortality in children. There are currently limited options for therapy, consisting of surgical resection, radiotherapy in patients over 36 months, and chemotherapy. SHH-subtype medulloblastoma arises from a particular cell type in the cerebellum called the Granule Cell Progenitor (GCP) and accounts for 30% of all MB. It tends to arise in very young children and have a poor prognosis. In this grant we have discovered a critical resilience mechanism that is required both for the survival of GCPs in normal developing cerebellum as well as for medulloblastoma arising from these GCPs. GCPs undergo an incredible expansion in cell number in the cerebellum during normal development, but are highly vulnerable to DNA lesions during this highly proliferative period . We have identified a transcription factor, Activating Transcription Factor 4 (Atf4), that is critical for survival of developing GCPs and normal cerebellum development. It acts as master regulator of the cellular DNA damage response, a system of cell responses to repair DNA damage and maintain cellular genomic integrity. In the absence of Atf4, GCPs die from a massive accumulation of DNA damage. Critically, we also show that in addition to a requirement for Atf4 for repairing DNA damage in developing GCPs, it is also required for DNA lesion repair in medulloblastomas arising from GCPs, and for the survival of MB tumor cells. Genetic loss of Atf4 in a mouse model of medulloblastoma doubles lifespan, with tumor cells dying with accumulation of DNA damage. This finding allows us to identify new therapeutic approaches for MB that significantly prolong life, targeting Atf4’s role in the tumor cell DNA damage response. This project will provide critical new insight into this devastating childhood brain tumor, and a novel avenue for therapeutic intervention.
In this grant we will 1) demonstrate a novel requirement for the transcription factor Activating Transcription Factor 4 (Atf4) for survival of Granule Cell Progenitors (GCPs) in the cerebellum, with an almost complete failure of normal cerebellum development in its absence. We will show that Atf4 acts as a novel master regulator in the DNA Damage Response in these cells. Critically, we will also show that 2) in addition to a requirement for Atf4 for repairing DNA damage in GCPs in development, it is also required for DNA lesion repair in medulloblastomas arising from GCPs, and for the survival of tumor cells. In a mouse model of medulloblastoma we will show that loss of Atf4 function doubles the lifespan of mice. We will identify new therapeutic approaches for MB, targeting Atf4’s role in the tumor cell DNA damage response.