Cellular Mechanisms Underlying Pediatric Glioblastoma: Heterozygous Mutations in Histone H3.3 Induce Chromosome Instability by Abolishing Ser31 Phosphorylation
Abstract
This study will focus on pediatric brain tumors and the militarily relevant risk factors associated with cancer (e.g., ionizing radiation, chemicals, infectious agents, and environmental carcinogens). The collection of diseases, known as cancer, is the result of cells in our bodies that have lost their ability to control their own proliferation. Instead of these cells remaining within the confines of their respective tissue, and only dividing when it is necessary, cancer cells divide uncontrollably. They eventually acquire aggressive characteristics, physically crawling into other tissues in a process called “metastasis.” The underlying questions related to the biogenesis of cancer are: (i) How do cancers acquire changes making them cancerous in the first place and (ii) how do they acquire subsequent changes that cause their aggressive behaviors? One potential cause for cancer development is mistakes during cell division (going from one cell to two cells) causing re-arrangements of chromosomes. This is called “chromosome instability.” We know that all cells arise for the division of a pre-existing parent cell. This process – called mitosis – involves the precise segregation of pairs of duplicated chromosomes in two cells – two sets of chromosomes are segregated exactly to the two daughter cells; each daughter cell must receive exactly one copy of each chromosome. If there is a mistake in cell division and a cell loses a chromosome, then it will lose the functions of all genes on that chromosome – there is no way for a cell to replace a lost chromosome. Some of those genes may be “tumor suppressors,” which function to prevent cancer. Lose one of these, and the chances of cancer go up. If a daughter cell gains a chromosome, it gains extra copies of those genes, which may promote tumor formation – these are called “oncognenes.” Gain an extra copy of one of these, and the chances cancer go up as well. Examination of tumors has revealed that by the time these have become cancerous, they have imbalanced chromosome numbers, meaning that they have lost or gained whole chromosomes. Our task is understanding how these cells make mistakes during mitosis that lead to this imbalance. If we can understand the nature of mitotic defects, then we can design treatment strategies to destroy these cells. Several chemotherapies target mitotic mistakes. We can also use this knowledge to prevent the onset of brain cancers in the first place and to design highly sensitive detection methodologies to identify pediatric brain cancer before it progresses and chemoprevention therapies to prevent them from becoming the high-grade tumors that are so dangerous. The good news is that cells in our bodies have several chemical pathways that ensure chromosome missegregation can’t happen. And even if it does happen, there are “fail-safe” mechanisms to prevent damaged cells from growing and dividing again. These “fail-safe” mechanisms normally keep our cells safe from chromosome instability. We know these exist, because if we experimentally make a cell gain or lose a single chromosome, the two daughter cells stop growing, whereas the surrounding “normal” cells continue. But there is bad news too. Environmental factors, many associated with active military service, can cause irreversible changes to cells. These are called “mutations,” and they can change how a cell responds to a potential problem, like chromosome instability. In fact, several recent studies have identified mutations that lead to pediatric brain cancers. But we don’t know how these changes affect cells – that is the goal of my proposal. The experiments outlined in my proposal are designed to test several of the proposed models that can explain how mitotic mistakes can contribute to brain cancer progression. Importantly, we seek to identify mechanisms that are linked to the true physiology of human disease, rather than simply study experimentally induced mitot
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810493
Entities
People
- Edward Hinchcliffe
Organizations
- United States Army
- University of Minnesota