Abstract 2578: GDF15 reprograms the microenvironment to drive the development of uveal melanoma liver metastases

Abstract Little is known about how interactions between the uveal melanoma (UM) and host cells in the tumor microenvironment (TME) drive the progression of liver metastases. Single cell RNA-seq analysis of UM samples identified marked differences in cell-cell communication between primary and metastatic UM characterized by increased signaling strength and numbers of interactions emanating from the hepatic stellate cells (HSCs) and endothelial cells in the metastatic samples. In co-culture, HSCs modulated the transcriptional heterogeneity of the UM cells, enriching for cell states that expressed genes implicated in cell survival, metabolic reprogramming and the angiogenic response. Co-culture of HSCs and UM cells also led to increased expression of growth factors and receptors implicated in angiogenesis including IL-8, VCAM1, VEGF and ICAM1. One candidate driver of HSC reprogramming was the TGF-beta family member GDF15. Increased expression of GDF15 was associated with a Class 2 metastatic UM phenotype in clinical UM samples and UM cell lines, with silencing of BAP1 in UM cells increasing both GDF15 expression and H3K27ac marks at the GDF15 promoter. Treatment of HSCs with GDF15 led to increased expression of multiple ECM proteins, inflammatory cytokines and angiogenic factors, including IL- 8. Both exogenous GDF15, IL-8 and conditioned media from UM-HSC co-cultures increased endothelial cell network formation in vitro, an effect that could be blocked by anti-GDF15 antibodies. In an eye->liver metastasis model of UM, silencing of GDF15 did not prevent the seeding of UM cells to the liver, but did inhibit the outgrowth of metastatic lesions. Although the GDF15-silenced UM cells were proliferative they did not recruit endothelial cells, leading to a significant reduction in metastatic burden. In sum, we provide the first evidence that UM liver metastasis development is dependent upon GDF15-mediated remodeling of the liver microenvironment leading to an angiogenic response that supports tumor growth. Citation Format: Sathya Neelature Sriramareddy, Navya Siddarajappa, Thanh Nguyen, Jeffim Kunetsov, Stefan Kurtenbach, James Jarad Dollar, Jonathan D. Licht, Ann Y. Chen, William J. Harbour, Keiran S. Smalley. GDF15 reprograms the microenvironment to drive the development of uveal melanoma liver metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2578.