Dissecting Inter-Compartmental Tumor-Host Communication Driving Early Dissemination in Uveal Melanoma.

Uveal melanoma (UM) is a rare cancer of the eye that often spreads to the liver, with few treatment options once metastasis occurs. While genetic features like monosomy 3, BAP1 loss, GEP class 2, and PRAME expression help identify high-risk tumors, we still don’t fully understand how these tumors spread—especially how they interact with and influence other parts of the body before metastases are visible. This project aims to better understand how UM tumors send signals across different biological compartments— within the eye, into the bloodstream, and through circulating cells. We’re building on a prospective, longitudinal cohort of over 100 newly diagnosed patients, collecting samples from the tumor, aqueous humor (the fluid in the eye), plasma, and peripheral blood at multiple timepoints. By analyzing extracellular vesicles, soluble proteins, and rare circulating cell types, we hope to map how signals move and evolve over time and space. In Aim 1, we’ll examine how high-risk tumor features shape the local environment of the eye. Aim 2 will follow changes in plasma to understand how signals originating in the tumor show up systemically. Aim 3 focuses on rare circulating cells, using advanced imaging tools to determine how these cells reflect or respond to cross- compartment signaling. We’ll integrate data from all compartments and timepoints to define communication “states” that may help explain why some tumors spread early. This will be the most detailed study of its kind in UM. By focusing on communication between compartments— not just single markers—we hope to gain new insight into how early spread happens, and how it might be detected or interrupted before metastasis occurs. These findings could lay the groundwork for future strategies to monitor high-risk patients or develop early intervention approaches. Because UM is a rare cancer with few large-scale, mechanistic studies, this work may also inform approaches for other cancers with low mutational burden and limited immune responsiveness. The project aligns with NCI’s priorities for rare cancer research and directly addresses the goals of NIH Notice NOT-CA-25-010, which encourages innovative, liquid biopsy–based studies of tumor–host communication. Project Number: 1R01CA311805-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Liya Xu | Institution: CHILDREN'S HOSPITAL OF LOS ANGELES, LOS ANGELES, CA | Award Amount: $573,286 | Activity Code: R01 | Study Section: Molecular Cancer Diagnosis and Classification Study Section[MCDC] View on NIH RePORTER: https://reporter.nih.gov/project-details/11343371