Researchers create new model for studying earliest stages of retinoblastoma

Scientists at St. JudeChildren’s Research Hospital have created a lab model for studying retinoblastoma, powered by hereditary mutations in the RB1 gene. Retinoblastoma is a rare cancer of the retina, the thin tissue at the back of the eye.

The researchers created organoid models for retinoblastoma that closely mimic the biology of tumors in patients. These models are an important resource for studying the earliest stages of the disease and for screening new therapies. The findings were recently published in Nature Communications.

Retinoblastoma occurs in very young children, and in some cases, children are born with the disease. Hereditary mutations in RB1 are one reason why this happens, but how these tumors arise and what other factors underlie their development remains difficult to study.

Retinoblastoma is also unusual because it is one of the few cancers that is not diagnosed by taking a biopsy of a tissue sample. This is because the process can help the tumor cells spread outside the eye. That means the tumor samples that researchers have access to come from cancers that have progressed beyond their earliest stages and require eye removal.

What we have developed with these retinoblastoma organoids is, for the first time, a laboratory model in which it is possible to study the processes that take place when retinoblastoma starts to form. We can follow the process from the beginning to the early stages of tumor development, which is really exciting and opens new avenues for research.”

Michael Dyer, co-corresponding author of the study, chair of the Division of Developmental Neurobiology, St. Jude Children’s Research Hospital

The need for a new model

Models provide scientists with a way to study disease in the lab, both its biological underpinnings and the way it responds to potential therapies. Creating models that reflect the reality of disease in human patients is a huge challenge. For rare diseases such as retinoblastoma, there are additional hurdles due to the limited number of patients. Retinoblastoma models, including cell lines, genetically engineered mouse models, and patient-derived xenografts, have been useful for research. However, these models have also failed to replicate the disease as it occurs in patients.

A particular problem for models created by knocking out or eliminating the RB1 gene is that while this mutation is a cornerstone of retinoblastoma in humans, mice with these abnormalities do not develop the disease. Previous research by St. Jude has shown that mouse models for retinoblastoma are not always reliable predictors for preclinical drug development studies.

“Understanding what else drives tumor development, BeyondRB1 could uncover new targets for therapy, influence disease treatment, and potentially halt the formation of new tumors,” said co-corresponding author Rachel Brennan, MD, St. Jude Department of Oncology. “If we uncover the mystery of what causes some patients to develop second tumors later in life, we can develop more effective screening programs and early interventions to save lives.”

Brennan leads the retinoblastoma clinical program with ocular oncologist Matthew Wilson, MD, University of Tennessee Health Sciences Center, who also co-authored the paper.

A better way to study the disease

To create a better model for research, the scientists grew so-called retinal organoids. These models are 3D cultures of cells made from induced pluripotent stem cells (iPSCs). The cells were created using samples from retinoblastoma patients with germline mutations in RB1. Grown and nurtured in the lab, iPSCs develop naturally into retinal tissue. The cells from the organoids were injected into mice, where retinoblastoma tumors eventually formed.

The researchers performed whole genome sequencing, RNA sequencing and methylation analysis of these retinoblastoma tumors and found that they were indistinguishable from patient samples.

“This is the first time we know where cells with a specific mutation have successfully grown into organoids and later spontaneously developed into tumors,” said first author Jackie Norrie, Ph.D., St. Jude Department of Developmental Neurobiology. “The ability of the organoid models to do this is unique, as cell lines with RB1 mutations do not spontaneously develop into retinoblastoma tumors. This underlines that both the RB1 mutation and the processes involved in the natural development of the retina have a role play in the formation of this cancer.”

Through their work, the researchers created a large dataset of retinoblastoma single-cell analysis results. These data, in addition to the researchers’ other work with patient tumors, patient-derived xenografts, and the organoid models, are freely available through the Childhood Solid Tumor Network (CSTN). The CSTN is a resource available to researchers worldwide that provides the world’s largest and most comprehensive collection of scientific resources for researchers studying pediatric solid tumors and related biology.


St. Jude Children’s Research Hospital

Reference magazine:

Norrie, JL, et al. (2021) Retinoblastoma of human stem cell-derived retinal organoids. Nature Communication.

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