Dissecting Functional uORFs as a Source of Cancer Genes in High-Risk Medulloblastoma
I have recently described an uncharacterized aspect of gene activity, which may operate downstream of MYC in medulloblastoma. Specifically, I have found that the human genome produces thousands of unstudied proteins from the regions of gene regulation where MYC operates. These unstudied proteins, which are called upstream open reading frames (uORFs), may have unique roles in medulloblastoma. I have worked to study these proteins in medulloblastoma and define their functions in this terrible childhood cancer.
The long-term aspiration of this project is to catalyze this line of research for medulloblastoma, in order to open up a new vanguard of cancer target genes in this disease, which may themselves become future clinical tools or drug targets. uORFs are a numerous population of uncharacterized proteins. Their importance in diseases, including medulloblastoma, is only beginning to be understood. My hope is that this project will provide the initial evidence that this class of proteins is critical in medulloblastoma, and thereby spur increasing interest in their ability serve as clinically-important genes. By doing so, this work may inspire new efforts to develop cancer biomarkers, clinical cancer subtypes, or drug targets for children with aggressive medulloblastoma.
Project Update 2024:
Our project focuses on the biological basis for the most aggressive type of medulloblastoma, a childhood brain cancer. Children with this aggressive type -- termed Group 3 – have a 50% chance of relapse, and once relapsed cure is very difficult to achieve. We have found that the central biological driver of this disease, a gene called MYC, has a new form of activity that has not been investigated before. We observe that MYC causes changes in the way in which these cancer cells convert genetic material (RNA) into functional proteins. This process is called RNA translation. We find that MYC creates distinct patterns of RNA translation in medulloblastoma. Moreover, MYC causes medulloblastoma cells to produce unusual or new types of proteins as well. We call these non-canonical open reading frames. We have found that these new types of genes can be critical to the survival of medulloblastoma cells, and that targeting them may be a new therapeutic approach for patients. We have focused on a compelling candidate that we call ASNSD1-uORF. This is a new gene that makes a new protein. It is required for medulloblastoma cells to survival. We find that this ASNSD1-uORF coordinates a complex network of biological activity that is rooted in regulating how medulloblastoma cells grow and divide. We can verify this in patient samples as well, where we find the same associations that we see in model systems. This work has lead to a manuscript that has been accepted for publication in 2024. We are very excited to continue to work on this project and delve more deeply into the ability to target ASNSD1-uORF and understand its role in promoting medulloblastoma cell growth.