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These advances are critical to faithfully mimic human cancer in the mouse, says Tyler Jacks, an HHMI investigator at the Massachusetts Institute of Technology, because the effects of cancer-associated mutations can depend on the specific type of cell or tissue in which they occur. "Making accurate cancer models requires a good deal of subtlety," says Jacks. "It's important to match the relevant mutations to the appropriate cancer and to pay attention to details ranging from the timing of the mutations to the levels of expression."
Jacks studies an oncogene called K-ras whose activation has been linked to many different cancers. His group recently developed two mouse models of lung cancer involving K-ras that come close to mimicking spontaneous human disease. One strain of mice has an inactive K-ras gene in its cells; a second strain has an inactive K-ras gene plus a tampered-with version of the tumor suppressor gene p53. The genes are engineered in such a way that when triggered—by the introduction of a virus, for example—the oncogenes can be turned on or the tumor suppressor can be turned off, thereby tripping the cellular overgrowth characteristic of cancer. This scenario—mutations in multiple genes, occurring in particular tissues and at particular times in the animal's life span—simulates what we know about cancer initiation in humans.
"That's a powerful tool in the study of lung cancer," says Jacks, "because we are interested in using these models to explore tumor progression, even from the earliest points." In June 2005, his group published a paper in Cell identifying a stem cell within the lung as the origin of non-small-cell lung cancers. "We wouldn't have been able to do that without use of sophisticated mouse models to control the initiation of tumor development." 
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