Cancer Biology, Molecular Biology
Massachusetts Institute of Technology
Dr. Jacks is the David H. Koch Professor of Biology and the director of the David H. Koch Institute for Integrative Cancer Research at MIT.
The Use of Gene Targeting in the Mouse to Investigate Cancer Genes
In high school, Tyler Jacks dismantled two nonworking Volkswagen Beetles to see how the various parts functioned. "Now I'm doing the same thing at the cellular level," says Jacks, who takes cancer pathways apart, step by step. Using novel mouse models or their cells, he tries to understand what cancer genes normally do and what happens when they are mutated.
Jacks began cancer research as a Harvard sophomore, when he studied leukemia cell lines. "I was enthralled with the power of molecular genetics and molecular biology because one could begin to manipulate cells in order to ask specific questions about gene expression control or cellular functions," he says.
By the time Jacks finished his postdoctoral work at MIT's Whitehead Institute, he had developed several mutant mice. One strain contained a faulty retinoblastoma gene, which is responsible for a rare childhood eye cancer. These mice could pass the mutation to their offspring, moreover. So when Jacks established his own lab at MIT in 1992, he decided to focus on these models and develop more. One of his most important contributions has been models that more accurately mimic human cancers. Thus, their mutations appear suddenly and only in certain cells, and those cells are surrounded by normal tissue. Previously, cancer genes had been expressed at abnormally high levels in animal models and were active in every cell of a target tissue.
One of the mouse strains developed by Jacks has a mutation in K-ras, which is mutated in 30 percent of human non-small-cell lung cancers, 40–50 percent of colon tumors, and 90 percent of pancreatic tumors. Therefore, understanding the molecular consequences of K-ras mutations and how they might be overcome could lead to huge effects on human health.
Because mice die before birth if K-ras is mutated in the germline, Jacks and his colleagues had to smuggle the faulty gene into embryos in an inactive form. They then waited for a rare, spontaneous event to activate the gene after the mice were born. The mice in which this happened developed several types of tumors, including lymphomas, skin cancer, and, most frequently, lung cancer. More recently, the researchers have modified this mouse so they can use a virus to unmask the K-ras mutation at an appropriate time. Therefore, they no longer have to wait for a chance event to generate this tumor model.
Scientists had assumed that K-ras mutations promote tumors because the resulting protein inappropriately activates downstream pathways. If that were the case, proteins in such pathways would be good targets for cancer drugs. But by studying several types of cancers, the Jacks group discovered that some of the well-studied downstream pathways of K-ras do not function abnormally in malignant cells. "This work highlights the fact that there is still a lot to be learned about how K-ras mutation contributes to tumor initiation and progression," Jacks says.
Perhaps his most important work involves p53, a tumor-suppressor gene that is mutated in most human cancers. Along with other groups, the researchers showed that p53 regulates cell division, preventing cells from dividing unrestrainedly. But Jacks also discovered that p53 causes cells that have damaged DNA to commit suicide by a process called apoptosis. So mutations in this gene not only promote cancer by permitting inappropriate cell division, they also allow cancer cells that have been badly damaged to inappropriately survive. "This work has important implications for the treatment of human cancer with DNA-damaging chemotherapeutic agents," Jacks says.
Recently, the group developed a mouse with a p53 gene that is silenced but can be switched on with the hormone analog tamoxifen. As expected, these mice developed tumors. But when they were injected with tamoxifen, the tumors regressed. "This establishes the important fact that, at least in this mouse model, p53 function remains relevant to even fully established cancers," Jacks says. He adds that several strategies for compensating for faulty p53 are already being tested in the laboratory and that one, p53 gene therapy, has been approved for human use in China.
Jacks attributes his success to his habit of thinking ahead instead of focusing only on the coming year. For example, he foresaw the need for more specific imaging technologies and, with collaborators at Massachusetts General Hospital, invested the time to develop an optical imaging method for detecting lung cancer cells at a very early stage. In 2005, he reported the use of an optical probe activated by protein-cutting enzymes that are highly active in such cells. More recent work from the group has shown that the same method can help guide surgery in a mouse model of sarcoma. "We hope this imaging method will be useful during surgery for detecting cancer cells that are often missed when a tumor is removed," Jacks says.
Deriving animal models also requires much forethought because new strains of mice can take years to perfect and tumors may take many months to appear. "The HHMI funding that I have received has been tremendously helpful in this respect because it has freed me to think downstream," Jacks says. His strong commitment to making a difference in the ability to diagnose and treat cancer has also been important. "I am quite hopeful that observations in this lab and others will impact how we are going to approach the disease and its management in the near future," he says. "I truly believe that we are turning the corner on cancer."