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 from 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 genes, and the chances of cancer go up. If a daughter cell gains a chromosome, it gains extra copies of those genes, some of which can promote tumor formation -- these are called "oncognenes." Accidentally gain an extra copy of one of these, and the chances of contracting 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 juvenile brain cancer before it progresses.

The good news is that cells in our bodies have several biochemical pathways that ensure chromosome missegregation can't happen. And even if it does happen sometimes, 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. Now we know the nature of the changes associated with these terrible diseases. But we don't know how these changes affect cells -- that is the goal of this proposal.

The experiments outlined in this 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 mitotic mistakes. These have the best chance of providing real insights into brain cancer development and lead to effective new treatments within 10 years.

We have made the observation that the genes found to be mutated in pediatric brain cancer are involved in normally preventing chromosome loss. Under these conditions, the cells make mistakes that should result in the activation of the "fail-safe." When the mistakes are not corrected for, like in developing brain cancers, the cells become abnormal and develop into tumors. We will study how these mistakes in chromosome segregation are linked to the mutations observed in patients. This is a new pathway for detecting mistakes in chromosome segregation. What makes this work innovative is that it involves cell components that we know to be damaged in pediatric brain cancer patients. This is a novel hypothesis and is not being tested elsewhere. The goal of modern molecular medicine is to identify cell components damaged in disease, understand how this affects cellular physiology, and then use this basic knowledge to design advanced diagnostic tools and effective therapeutic strategies. I am a basic cell biologist and want to use my knowledge of cellular mechanism to provide valuable information to bring to bear on real-world problems for patients. Without this basic knowledge, it is impossible to design new, effective treatments for these devastating diseases that greatly affect our service members and their families.