Approximately 50 years ago, it was discovered that normal human cells can only undergo a finite number of divisions before they stop dividing and enter a quiescent state known as senescence. Surprisingly, it was later shown that mutations that activate genes that promote cancer development, known as oncogenes, can also cause cells to enter a senescent state. This phenomenon of so-called "oncogene-induced senescence" is a major protective mechanism that suppresses cancer formation by preventing cells with mutated oncogenes from expanding and forming tumors. In most human malignancies, cells acquire other mutations that allow them to bypass this senescent state and proliferate in an uncontr...

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Approximately 50 years ago, it was discovered that normal human cells can only undergo a finite number of divisions before they stop dividing and enter a quiescent state known as senescence. Surprisingly, it was later shown that mutations that activate genes that promote cancer development, known as oncogenes, can also cause cells to enter a senescent state. This phenomenon of so-called "oncogene-induced senescence" is a major protective mechanism that suppresses cancer formation by preventing cells with mutated oncogenes from expanding and forming tumors. In most human malignancies, cells acquire other mutations that allow them to bypass this senescent state and proliferate in an uncontrolled manner.

We recently discovered that regulation of the process by which cells synthesize proteins plays a major role in oncogene-induced senescence. The ribosome, which is composed of RNAs and proteins, is the cellular machine that produces new proteins. In order for the ribosome to function properly, the cell chemically modifies the RNA inside of it, which assists with the complex protein synthesis process. Unexpectedly, we found that these chemical modifications of ribosomal RNA are critical for the entry of cells into a senescent state upon oncogene activation. Moreover, low levels of the cellular factors that install these modifications are observed in several types of human cancer, including lung cancer. Lung cancer patients whose tumors have low levels of these factors also have a worse prognosis. Based on these discoveries, we now propose to investigate the mechanism by which chemical modification of ribosomal RNA controls cellular senescence and the role of this process in lung cancer pathogenesis using cellular and animal models. These studies will illuminate an entirely new mechanism that impacts the development of lung cancer and other malignancies, and therefore have the potential to lead to new therapeutic strategies in the future.

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