Retinoblastoma Malignance and Exosome Mechanisms Facilitating Optic Nerve Head Metastatic Niche Formation

Author

Cui Shi, The Graduate Center, City University of New YorkFollow

Date of Degree

9-2024

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biochemistry

Advisor

Stephen Redenti

Committee Members

Julio Gallego-Delgado

Renuka Sankaran

Dianne Cox

Tatjana Jakobs

Subject Categories

Biochemistry | Molecular Biology

Keywords

Retinoblastoma; Extracellular vesicle; Pre-metastatic niche; Reactive astrocytes; Gene editing

Abstract

Retinoblastoma (RB) is a rare pediatric ocular tumor that occurs before five years of age and it is the most common intraocular cancer of childhood with more than 300 children in the United States and 8000 diagnosed globally each year. RB arises from the proliferation of cone photoreceptor precursor cells in the retina as a result of mutations in the RB1 gene. The influence of RB secreted factors on cells in the retinal environment has not been fully elucidated. Cancer cell released exosomes have been shown to transform their microenvironment through transfer of metastasis promoting molecular cargo. Cancer cell extracellular vesicles seed and transform microenvironments forming pre-metastatic sites that attract and enhance the survival of metastatic cancer cells. In this study, we investigated the role of retinoblastoma exosomes in the pathogenic transformation of the ocular microenvironment by driving changes in retinal astrocytes and retinal microvascular cells to support tumor growth and migration. Our results show that lymphocyte antigen 6 family member E (LY6E) protein, which presents exclusively in the metastatic retinoblastoma exosomes is a critical effector during this transformation process. Our data supports that RB-released exosomes containing LY6E drive inflammatory signaling in retinal astrocytes and break the integrity of tight junctions of retinal vascular endothelial cells in vitro. Following CRISPR knockdown of RB exosome-LY6E, analysis revealed a reduction of microvascular endothelial cell leakiness in vitro and astrocyte inflammatory signaling in vivo. This work provides novel data, describing RB exosome-LY6E-mediated pathogenic changes which may facilitate ocular tumorigenesis and metastatic niche formation.

Recommended Citation

Shi, Cui, "Retinoblastoma Malignance and Exosome Mechanisms Facilitating Optic Nerve Head Metastatic Niche Formation" (2024). CUNY Academic Works.
https://academicworks.cuny.edu/gc_etds/5973