Page 32 - The Hormel Institute 2024 Annual Report

32 | THE HORMEL INSTITUTE
// UNIVERSITY OF MINNESOTA
Despite considerable success in treating many types of cancers, pediatric brain tumors have shown stubborn resistance
to treatment—and they exhibit some of the worst outcomes of any cancer type.
Diffuse midline gliomas (DMGs) are a rare form of pediatric brain tumor that affect very young children, with an average age of 5 years at the time of diagnosis. Despite over 200 clinical trials, there is no effective treatment, and 1-year survival rates remain at less than 5%. Genome- wide sequencing of DMGs revealed that in ~80% of cases, heterozygous point mutations in a core histone H3 variant cause an amino acid substitution (Lysine-to-Methionine) at position 27. This K27M mutation acts as a driver for these tumors.
However, unraveling the mechanism that transforms this simple genetic change into gliomagenesis, the formation and development of gliomas, has been challenging. It is known that H3 Lys27 serves as a major contributor
to epigenetic regulation of gene expression, particularly during early development. The K27M mutation acts in a dominant fashion, globally suppressing K27 triple methylation, re-animating developmental gene expressing patterns and reverting cells to a stem-like state. But this is
not sufficient to drive gliomagenesis alone.
Our lab has been studying a novel facet of the H3.3K27M mutation not linked to its role in epigenetic regulation: its effects on phosphory- lation of the neighboring Serine 31. H3.3Ser31 phosphorylation plays important but cryptic roles in mitotic regulation. Supported by funds from the NIH, DoD Peer Reviewed Cancer Research program, the Minnesota-Mayo Partnership and the Marit Swenson Shining Light Foundation, our work has uncovered novel aspects of the role of H3.3 Ser31 phosphorylation in driving chromosome instability and its contribution to gliomagenesis.
We have recently shown that the H3.3K27M protein causes Chk1—the kinase responsible for Ser31 phosphorylation—to “stick” to the mutant histone, decreasing levels of phospho-Ser31. The result is increased chromosome instability and the generation of dynamic, varying karyo- types associated with aggressive cancers. We are currently exploring the role of Chk1 kinase in this process, and testing whether Chk1 inhibi- tors can act as radio-sensitizing drugs to treat early stage DMGs. Our work also suggests that cGAS-STING-mediated inflammatory micro- nucleation—a consequence of chromosome missegregation during mitosis—could be a target for anti-DMG therapy. We are currently testing STING agonists as potential anti-DMG agents.