Metastatic spread from primary eye tumor after enucleation in a Uveal Melanoma orthotopic human to mouse xenograft model

Abstract

Purpose : Uveal melanoma often leads to metastatic disease, especially to the liver. Current mouse models have difficulty mimicking the long latent phase and liver propensity of metastases in humans. Primary eye tumor growth often reaches endpoint criteria before metastasis can fully develop, resulting in orthotopic mice studies to end prematurely. We hypothesized that if the primary tumor is enucleated and the observation period can be increased, the resulting mouse model mimics human disease progression.

Methods : Suprachoroidal injection of 1x10^5 primary UM cells (MP41 and Mel285) are performed in NSG mice. Twelve weeks after primary tumor cell injection tumor-bearing eyes, livers, lungs and blood were collected to detect disseminated UM cells and micro metastasis. Detection was done by staining cryosections of the tissue for tumor markers (HMB-45 and Mart-1); flow cytometry was used to quantitate the tumor burden. To allow for longer metastasis growth in a second group of mice, the tumor-bearing eyes were enucleated at 12 weeks post-injection, with tissues collected and analyzed 6 weeks later as described above.

Results : MP41 and Mel285 express high levels of HMB-45 and Mart-1 human melanoma tumor markers detected by flow cytometry and tumor cell staining. After twelve weeks of primary tumor growth, immunofluorescent staining of eye, liver and lung tissue confirmed primary tumor development and single tumor cells and micro-metastases in livers and lungs. Six weeks post survival enucleation of the tumor bearing eye (18 weeks post injection) large and multiple liver metastases were detected.

Conclusions : This mouse model resembles the human disease progression of UM, where even if the primary tumor is enucleated or successfully treated, liver metastases can still develop years later. Therefore, it provides an opportunity to increase our understanding of metastatic disease progression and test various potential therapeutic targets.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.