Dissecting the Role of Polycomb Repressive Complex 1 in Uveal Melanoma Progression
Abstract
The Scholar s Career Goal Is in Melanoma Research: I am a physician-scientist with a research background in genetics and cancer research, and clinical training in ophthalmology. My laboratory at the Yale School of Medicine focuses on understanding the molecular basis underlying ocular melanoma metastasis with the goal of using this knowledge to develop novel therapies and improve patients’ survival. I have an outstanding career guide, Marcus Bosenberg, M.D., Ph.D., an established melanoma scholar whose research program has been funded by the NIH for the past 20 years, and with a long track record in mentoring junior investigators. My goal is to establish an independent, fully funded melanoma research program, and participation in the Melanoma Research Program (MRP) Melanoma Academy will be instrumental in helping me achieve this goal. Fiscal Year 2022 (FY22) MRP Focus Area(s) in Section II.A.I to be Addressed by the Research Project: (1) Research across the entire spectrum (biology, etiology, prevention, diagnosis and detection, prognosis, treatment, and quality of life) for rare melanomas (e.g., uveal, acral, mucosal, pediatric) in patients and model organisms. (2) Delineate the molecular pathways that influence metastatic spread, recurrence, and/or dormancy. This project addressed the FY22 MRP Challenge Statement, as it encourages research which aims to inhibit melanoma earlier in the disease progression to prevent metastasis and increase survival, and application of knowledge to address the need for improved understanding of rare melanomas. Scientific Rationale, Objective, and Aims for the Proposed Project: Uveal (ocular) melanoma, albeit rare, is the most common and lethal primary intraocular cancer in adults, metastasizing (spreading to distant organs) in nearly half of patients. Once uveal melanoma cells spreads to distant organs, patients rarely survive beyond 18 months. Unfortunately, survival rates for patients with metastatic uveal melanoma have not significantly changed over the course of the last five decades. Therefore, developing ways for interventions earlier in the disease cycle with the goal of preventing metastasis is a critical priority. This requires a better understanding of the molecular pathways that influence uveal melanoma progression and metastatic spread. Our work has identified that ocular melanomas contain tumor cells with different metastatic potential. We examined thousands of individual tumor cells from patients and analyzed their gene expression, which allowed us to discover a completely novel mechanism by which tumor cells can become more aggressive, and thereby more able to spread to distant organs. Gene activity is tightly regulated in the cell through epigenetic regulators. We found that loss of an important epigenetic protein complex called Polycomb Repressive Complex 1, leads to aberrant gene activity, errors in chromosome segregation during cell division, and a thwarted inflammatory response which enhances the metastatic potential of tumors. The discovery of these key steps necessary for tumor progression gives us an opportunity to target them with therapies with the goal of preventing metastases. In this project, I propose to validate this hypothesis using advanced and targeted genetic editing, wherein we selectively disrupt different components of the Polycomb Repressive Complex 1 and assess the changes that occur to the genes levels and cell shape. This will allow us to precisely delineate the key components that are necessary for progression towards an aggressive phenotype. We will then establish mouse models to demonstrate that this phenotype translates into increased ability for the cell to spread to distant organs. We will use established uveal melanoma cancer cells as well as cells that are freshly derived from tumor specimens. These models reflect a spectrum of the intratumoral heterogeneity and are both biologically and clinically relevant. Ap
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252311070
Entities
People
- Mathieu Bakhoum
Organizations
- United States Army
- Yale University