Transcriptomics,Genomics

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A three-dimensional organoid model recapitulates tumorigenic aspects and drug responses of advanced human retinoblastoma


ABSTRACT: Persistent or recurrent retinoblastoma (RB) is associated with the presence of vitreous or/and subretinal seeds in advanced RB and represents a major cause of therapeutic failure. This necessitates the development of novel therapies and thus requires a model of advanced RB for testing candidate therapeutics. To this aim, we established and characterized a three-dimensional, self-organizing organoid model derived from chemotherapy-naïve tumors. The responses of organoids to drugs were determined and compared to relate organoid model to advanced RB, in terms of drug sensitivities. We found that organoids had histological features resembling retinal tumors and seeds and retained DNA copy-number alterations as well as gene expression profile and protein expression of the parental tissue. Cone signal circuitry (M/L+ cells) and glial tumor microenvironment (GFAP+ cells) were primarily present in organoids. Topotecan alone or the combined drug regimen of topotecan and melphalan effectively targeted proliferative tumor cones (RXRg+ Ki67+) in organoids after 24-h drug exposure, blocking mitotic entry. In contrast, methotrexate showed the least efficacy against tumor cells. The drug responses of organoids were consistent with those of tumor cells in advanced disease. Patient-derived organoids enable the creation of a faithful model to use in examining novel therapeutics for RB. Overall design: Samples from human retinoblastoma organoids [2 samples from passages 1 (6-week culture) and 3 (13-week culture)] and retinoblastoma tissue [the tumor tissue used for culture (1 sample)] were used to generate RNA-seq libraries. Gene expression profiles were generated by sequencing using NovaSeq6000. Published gene expression profiles of fetal retina (2 samples, days 132 and 136 from Hoshino et al., 2017; Dev Cell; 43(6):763-779.e4) and retinoblastoma (1 sample from Aldiri et al., 2017; Neuron; 94(3):550-568.e10) were included for analysis. The three reanalyzed samples are included in supplementary file kaewkhaw.tumor.organoids.668.Hsap38.Ens82.gene.CPM.tsv linked at the foot of this record.

INSTRUMENT(S): Illumina NovaSeq 6000 (Homo sapiens)

SUBMITTER: Rossukon Kaewkhaw 

PROVIDER: GSE120710 | GEO | 2018-10-23

REPOSITORIES: GEO

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Publications

A three-dimensional organoid model recapitulates tumorigenic aspects and drug responses of advanced human retinoblastoma.

Saengwimol Duangporn D   Rojanaporn Duangnate D   Chaitankar Vijender V   Chittavanich Pamorn P   Aroonroch Rangsima R   Boontawon Tatpong T   Thammachote Weerin W   Jinawath Natini N   Hongeng Suradej S   Kaewkhaw Rossukon R  

Scientific reports 20181023 1


Persistent or recurrent retinoblastoma (RB) is associated with the presence of vitreous or/and subretinal seeds in advanced RB and represents a major cause of therapeutic failure. This necessitates the development of novel therapies and thus requires a model of advanced RB for testing candidate therapeutics. To this aim, we established and characterized a three-dimensional, self-organizing organoid model derived from chemotherapy-naïve tumors. The responses of organoids to drugs were determined  ...[more]

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