Abstract 7569: Characterizing pathways for metastasis of retinoblastoma in forebrain organoids

Abstract

Abstract Retinoblastoma (Rb) is a childhood cancer of the eye, which usually presents in children under the age of five. When detected early, Rb has favorable prognosis in developed countries, but metastasis into the central nervous system (CNS) through the optic nerve correlate with a high mortality rate. Even if detected early, the available harsh and unspecific treatments can cause serious side effects, and enucleations are still performed frequently. There is still uncertainty regarding the mechanism for metastasis into the central nervous system. We performed bioinformatic analysis of single cell sequencing data for retinoblastoma, retinal tissues, optic nerve, and brain, to identify potential pathways and cell-cell communications fostering Rb invasion into the optic nerve and brain. Our analysis revealed several potential metastatic drivers, including immune modulation involving MIF, secreted by the Rb cells, as well as cell-adhesion pathways promoting a change in cellular phenotype. Given that animal models do not faithfully recapitulate human Rb initiation and progression, we developed a novel human iPSC-derived forebrain organoid model to investigate mechanisms of Rb CNS metastasis. Microinjections of GFP-labelled Rb cells allow to track growth and spread. In this fully human model including microglial cells, we can, for the first time, study the Rb forebrain interactions and pathways involved. RNA-seq analysis of Rb cells growing in forebrain organoids shows increased activity in neuron projection development and neuron migration, overlapping with the observed phenotype switch of invading Rb. Together, we present a novel iPSC-derived human forebrain model to monitor growth and spread of metastatic Rb, and describe new pathways involved in invading and metastasizing Rb. Citation Format: Yulia Shtanko, Sara Rodriguez, Benjamin Schachner, Emily Adis, Samantha McLaughlin, Sebastian Borges, James Dollar, Ashley Zuniga, Gabriela Quintana, Sofia Lopez, Dawn Owens, Chloe Moulin, Steffanie Braun, Gulum Yenisehirli, Daniel Pelaez, J. William Harbour, Stefan Kurtenbach. Characterizing pathways for metastasis of retinoblastoma in forebrain organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7569.