Monte M. Winslow, Ph.D.

Abeloff V Scholar*

Lung cancer is the leading cause of cancer deaths in both men and women in the United States, with over 155,000 patients dying each year. Several factors contribute to the poor outcome of lung cancer patients, but as in most tumors, the ability of cancer cells to leave the primary tumors and establish inoperable metastases is a major impediment to successful therapy. We have identified a key regulator or lung cancer metastasis. This protein, named Nkx2-1, suppresses metastasis and cancers, which at first express Nkx2-1, must evolve to loss Nkx2-1 prior to metastasis. Nkx2-1 is a certain type of protein that binds to the genome and controls the expression of other proteins therefore we are interested to figure out what those proteins are and which of them are critical regulators of metastasis. My V Foundation Scholar award has been critical for my laboratory work to uncover these components that drive lung cancer to its lethal metastatic state. My laboratory has developed genetically-engineered mouse models of human lung cancer that enable us to alter proteins in tumors and assess their impact on metastasis. We are using these methods to investigate the proteins controlled by Nkx2-1 with the hope that this project will enable a better understanding of lung cancer metastasis. Our work may have important implications for early lung cancer detection and therapies directed at inhibiting metastasis formation and treating metastatic disease.

Gang (Greg) Wang, Ph.D.

Abeloff V Scholar*

Enzymes that modify chromatin (the physiological form of DNA) are often found abnormally expressed, mutated, and/or hyper-activated among various forms of blood malignancies. Somatic mutations of EZH2, a gene that encodes a critical chromatin-modulating enzyme, are responsible for over 10-20% of clinically diagnosed diffused large B-cell lymphomas and follicular lymphoma. These mutations are known to lead to EZH2 hyperactivity in cancer cells. However, it is largely unclear how EZH2 is associated with chromatin, which is critical for EZH2’s role in gene control and cancer promotion. Using the biochemical approach as a discovery tool, we demonstrate that the activities of EZH2 rely on a critical interacting factor PHF19 or PHF1, which opens a possibility for pharmacological manipulation and makes them ideal drug targets. Abnormalities of both PHF1 and PHF19 have been frequently found in human cancers including lymphoma patients, which resonate well with their roles in regulating EZH2 during cancer development. Future investigation shall be performed to design new ways for targeting EZH2’s cofactors as novel anti-cancer interventions.

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