Pre-doctoral Fellowship Grant Awarded to Caroline Hanson

Diffuse midline gliomas (DMGs) are lethal tumors driven by early stage ‘stem-like’ cells that normally mature (or differentiate) into more specialized cells in the brain. Normal differentiation is facilitated by changes in how DNA is spooled around DNA packing proteins (histones), altering accessibility and expression of gene programs to suppress stemness and promote differentiation. However, in DMG, histones contain mutations that alter histone organization and gene expression, resulting in stalled differentiation and persistence of stem-like tumor
propagating cells. Strategies that alter this aberrant histone organization can block DMG growth by inducing differentiation. We recently discovered that a specific set of lipids can similarly ‘coax’ DMG stem-like cells to differentiate. Moreover, diet-based strategies to enrich these lipids in the brain slow DMG growth in pre-clinical models. By using cutting-edge proteomics technology, we have also found that this differentiation process is dependent on the activity of a mediator protein known to regulate gene accessibility. The proposed studies will explore the molecular details of this process. In our first aim, we will examine the functional relevance of the identified mediator protein in the differentiation process. Using state-of-the-art approaches, we will interrogate lipid-dependent interactions of this mediator protein with DNA and their consequences on gene programs related to stemness versus differentiation. In the second aim, we will identify direct targets of these lipids that initiate DMG differentiation using innovative chemical tools that resemble and function like these lipids. We will use these tools to capture proteins that bind these lipids in DMG cells. We will then determine how the identified lipid binding proteins work in concert with the mediator protein to promote DMG differentiation. By characterizing lipid
dependent pro-differentiation mechanisms that reduce stem-like tumor propagating cells in DMG, our proposed studies have the potential to reveal novel strategies for restricting the growth of these aggressive tumors.