Principal Investigator Jacqueline Lees is the Virginia & D.K. Ludwig Professor for Cancer Research.

A main research focus of the Lees Laboratory is uveal melanoma, the most common primary malignancy of the eye in adults. While primary tumors are highly treatable, roughly half of patients develop metastatic disease, which is essentially lethal.

Uveal melanoma arises from transformed melanocytes in the uvea, or pigmented layer, of the eye. Most human uveal melanomas have activating mutations in a small number of genes that involve or intersect GNAQ/11 signaling pathway. These mutations are entirely different from the common driver mutations of melanoma of the skin, arguing that these are different diseases and explaining why effective therapies for melanoma of the skin fail against uveal melanoma.

Using zebrafish models the Lees Laboratory is investigating the molecular mechanisms underlying the development and progression of uveal melanoma, and aims to identify candidate targets for therapeutic intervention. When one of the key patient-derived tumor mutations affecting GNAQ/11 unexpectedly failed to promote tumors in this system, the Lees group showed that activated, nuclear YAP—an alternative downstream pathway of GNAQ/11—can efficiently drive zebrafish uveal melanomas. Activated YAP is a hallmark of human uveal melanomas, supporting a key role for this pathway.

Levels of a transcription factor called Mitf play a profound role in development and therapeutic response of melanoma of the skin, and inhibition is considered a potential therapeutic approach. Using zebrafish models, the Lees group found that, in stark contrast, Mitf loss enhances development of uveal melanoma driven by GNAQ or YAP. Thus, in uveal melanoma, Mitf functions as a tumor suppressor, and is not a therapeutic target. Ongoing studies are assessing whether Mitf loss modulates activity of the known oncogenic pathways and/or provides new signaling events.

Search PubMed for Lees Lab publications