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Waking Cancer Cells to Eliminate Them

Stephen Lee, Ph.D.

Cancer cells have a bagful of tricks to escape treatment, including going to sleep. Because radiation and chemotherapy target fast-growing tissue, senescent cells can pass through unscathed, sometimes waking up years later to fuel new tumors.

But now, in a paper, “A Translational Program that Suppresses Metabolism to Shield the Genome,” published November 13 in Nature Communications, a research team led by Stephen Lee, Ph.D., a member of the Tumor Biology Program at Sylvester and professor of biochemistry and molecular biology at the Miller School of Medicine, has delineated a key mechanism driving cellular senescence. These findings could lead to more effective treatments for cancer and other diseases.

“Tumor cell dormancy has been quite enigmatic,” Dr. Lee said. “Surgeons remove the primary tumor and, five years later, the patient develops metastases. Oncologists throw radiation and chemotherapy at them, but they’re highly resistant because they’re metabolically inactive. But if we can prevent these cancer cells from entering dormancy, it’s likely they will act like normal cancer cells and respond to treatment.”

Dr. Lee’s team studied cancer cells in hypoxic (low oxygen) and acidic conditions — much like tumor microenvironments. They found that a molecular pathway, centering on the protein eIF5A, responds to these conditions and triggers senescence.

Unlike transcription factors, which tell genes to produce RNA, eIF5A is a translation factor that reconfigures how RNA machinery produces proteins. Once this program is turned on, the cell goes to sleep, only to be awakened by some future, currently unknown, molecular signal.

“It’s a protein synthesis response that results in a very powerful process that triggers cellular dormancy,” Dr. Lee said. “Under these conditions, cells not only stop proliferating, they also shut down all metabolic processes.”

While this particular study focuses exclusively on cancer, Dr. Lee notes the process works both ways — cellular senescence could be triggered as a therapeutic measure, for example, to reduce the damage from a stroke.

“My job is to study cancer, but this mechanism does not apply only to cancer,” he said. “It could be applicable to ischemia, stroke, heart attack and even early embryonic development.”

The Lee lab will continue to study novel mechanisms associated with senescence and other cellular functions. However, the findings from this study could ultimately lead to new therapies that discourage cells from going to sleep or even keep them dormant much longer, preventing them from spawning new tumors.

“This opens up many different avenues of investigation because the central protein in this mechanism happens to be druggable,” Dr. Lee said. “And it’s not just one protein; it’s a pathway, so there are a lot of potential targets in there. In fact, there are already clinically available drugs that target this pathway.”