Scientists have long attempted to puzzle out the enigma that is cancer. Over the last decade, geneticists and others have taken to analyzing thousands of tumors of all types, using high throughput genomic technology that seeks to find all the genes that are mutated across cancers. While these methods generate lists of affected genes, understanding what those mutations contribute to the actual occurrence of cancer is much more difficult to grasp.
“A few genes are very commonly mutated in various cancers, but many others are mutated at very low frequencies,” says John C. Schimenti, Biomedical Sciences. “The big question has always been which of these genes, when mutated, are the drivers that cause cancer, and which are merely ‘passengers’ that have nothing to do with the disease.”
Understanding the Function of the Gene Mcm4 in Starting Cancer
In an effort to find answers, the Schimenti Lab is engaged in multiple projects addressing the role played by the gene Mcm4 in cancer genesis. Originally discovered in the early 2000s by Cornell Professor Emeritus Bik-Kwoon Tye, Molecular Biology and Genetics, Mcm4 is essential for the unwinding of a cell’s DNA double helix, the first step in DNA replication during cell division. Soon after Mcm4’s discovery, Schimenti and his colleagues isolated a mutation in mouse models, called Chaos3, that carries a partially impaired Mcm4 gene. This mutation causes them to have a 20-fold increase in genomic instability, making them accumulate mutations and chromosomal aberrations during DNA replication and cell division.
“Tumor cells with genomic instability and uncontrolled growth are hallmarks of cancer,” Schimenti explains. “While the Mcm4 mutation doesn’t itself cause cancer, it confers the genomic instability hallmark, which increases the odds of mutations in other genes that then cause cells to grow out of control. Chaos3 mice look normal, but eventually they all get cancer. They don’t replicate DNA with normal high fidelity.”
The Gene Arid1a, a Potential Driver of Breast Cancer
Chaos3 mouse models are prone to cancers of all types, but in a certain strain, the females end up with mammary tumors, the equivalent of human breast cancer. Knowing this, Schimenti and his colleagues use a series of strategies to try to assess which gene mutations in the tumors are actually the ones causing breast cancer. In one finding, they showed that a gene called Arid1a that is commonly mutated in many cancers may be a driver of breast cancer. “This gene is frequently mutated in our mouse model tumors,” Schimenti says. “We thought insufficiency of Arid1a, it could be a driver. So one of our strategies to cure tumor cells of uncontrolled growth is to restore normal levels of this gene.”
The researchers found that tumor cells with the Arid1a mutation grow very quickly in the lab, but when they inserted a good copy of the Arid1a gene back into the cells, the tumor cell growth slowed down. They then tested this treatment by transplanting tumor cells into normal mice. The cells grew into tumors, but when they inserted a good copy of the Arid1a gene into the cells first before implantation, the tumors did not grow. “These are the types of assays we use to try to validate our hypotheses concerning which genes are the real cancer drivers,” Schimenti says.
What Happens When a Cell Stops an Incorrect Replication Process?
Another line of research for the Schimenti Lab centers on checkpoints in the process of DNA replication. These are mechanisms by which a cell senses that replication and division is not proceeding correctly and stops the process to assess the situation. The cell will then either repair the mistake or conclude there is too much damage to fix and undergo a natural process of cell death.
Schimenti is especially interested in the checkpoints that operate in germ cells such as oocytes, the eggs that female mammals carry in their ovaries. Over the past few years, he and his colleagues have pinpointed the key checkpoint genes involved in genetic quality control of oocytes. Investigating how these checkpoint genes work, the researchers used chemicals to inhibit them while exposing mouse models to radiation. They were surprised to discover that inhibiting the genes not only prevented the oocytes from dying but also protected their function. “We were able to show that if you apply a drug that inhibits these checkpoint genes before radiation, you can protect the oocytes; and they are still capable afterward of producing offspring,” Schimenti says.
“The prospect arises that in the future, rather than having their eggs frozen before chemo or radiation, women may be given these inhibitor drugs to protect their oocytes.”
Cancer Treatment and Infertility in Women—a Potential Solution
The researchers saw an application for their discovery in human oncology. They knew that one of the side effects of cancer treatment in women of child-bearing age is the destruction of their oocytes, which causes infertility and premature menopause. This happens because cancer treatments damage the eggs, and the checkpoint genes then trigger cell death. Currently, the only option for women undergoing cancer treatment who hope to have children later is to have their eggs extracted and frozen before treatment begins. “These inhibitor drugs specifically block the proteins encoded in the checkpoint genes that cause the death of the oocytes,” Schimenti explains. “The prospect arises that in the future, rather than having their eggs frozen before chemo or radiation, women may be given these inhibitor drugs to protect their oocytes.”
However, Schimenti cautions that much more testing needs to be done to ensure the eggs that are protected by the inhibitor are still viable for reproduction. “Evolution has dictated that these oocytes should be killed, and we’re subverting that,” he says. “This treatment option has to be tested for safety because we might be inducing mutations that would get passed on to progeny. We did protect the oocytes in our mice models and produced offspring that looked normal, but you have to be 100 percent certain.”
A Cancer Research Journey
Schimenti’s interest in the role genes play in cancer arose from a natural progression of research. “The first thing I worked on as a graduate student was the evolution of genes,” he says. “That led to an interest in the mechanisms causing gene duplication, which occurs by genetic recombination. Recombination is a process for repairing damaged DNA, so I wanted to know when that process gets messed up, how does that lead to cancer? How do we stop cancer once it starts?
“That led me to the checkpoint genes. The research progression was like a seed. It started with a little shoot, then branches kept growing off of it. There’s no end. These days, I try to envision what line of research has the highest potential impact. Can it have real-life importance for disease or result in truly important biological advances in our understanding? That’s the research I pursue.”