RB1 depleted pluripotent stem cell retinal organoids recapitulate state cell transitions of retinoblastoma development
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ABSTRACT:
PROVIDER: PRJNA725539 | ENA |
REPOSITORIES: ENA
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Project description:Retinoblastoma (Rb) is a childhood cancer of the developing retina that begins in utero in response to bi-allelic inactivation of RB1 or MYCN amplification, accounting for up to 1% of all tumours in infancy. To gain insights into the transcriptional events of each state cell transition during Rb development, we developed two Rb models via retinal organoid differentiation of RB1 depleted human embryonic stem cell line (RB1-null hESCs) and RB1patient-specific induced pluripotent (iPSC) line harbouring RB1 biallelic mutation (c.2082delC). Both models were characterised by RB1 depletion and a significant increase in the fraction of proliferating cone precursors (RXRγ+Ki67+), which were defined as cell of origin for Rb by the single cell RNA-Seq analysis. The RB1 depleted retinal organoids displayed similar features to Rb tumours including mitochondrial cristae aberration and rosette-like structures and were able to undergo cell growth in an anchorage-independent manner, indicative of cell transformation in vitro. The patient-specific iPSC model displayed an enhanced reduction of amacrine, horizontal and retinal ganglion cells and an accelerated loss of cone photoreceptor markers during transition towards retinoma and Rb, compared to RB1-null hESC. In both models, the Rb cells of origin, intermediate retinoma and/or Rb cells expressed retinal ganglion and horizontal cell in addition to cone markers, a novel finding, which should help to better identify and eradicate these cells within the tumour mass. Application of Melphalan, Topotecan and TW-37 led to a significant reduction in the fraction of proliferating cone precursors, validating the suitability of these in vitro models for testing novel therapeutics for Rb.
2023-03-03 | GSE173447 | GEO
Project description:Total RNA-seq with rRNA depletion in retinoblastoma protein 1 knockout (RB1 KO) IMR-90
2021-12-29 | GSE173127 | GEO
Project description:Retinoblastoma (Rb), the most prevalent intraocular malignant tumor in children with global survival rate less than 30%, is mainly caused by the deficiency of the tumor suppressor RB1. A line of evidence have shown that local inflammation and immune escape play important roles in the occurrence of Rb, however the underlying mechanism remains unclear. We hypothesize that the unique neuroimmune cell type, retinal microglia, has a vital role in the Rb pathogenesis. In this study, we differentiated microglia cells (iMGs) from established induced pluripotent stem cells (iPSCs) derived from a retinoblastoma patient with the defined RB1 mutations. We investigated the function of RB1 in innate immune response of microglia and found that the expression of interleukins and chemokines, especially interleukin 6 and TNF-α, were highly upregulated in LPS-stimulated RB1 deficient iMGs, which enhanced innate immune responses and created a pro-inflammation environment. These findings demonstrated that RB1 is indispensable to maintain microglia function in innate immunity and its deficiency leads to enhanced inflammation responses, which may accelerate tumor growth and malignancy. This study provides new insights for pathological mechanism and immunotherapeutic target of retinoblastoma.
2022-12-31 | GSE212248 | GEO
Project description:RB1 loss triggers dependence on ESRRG in retinoblastoma
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Project description:RB1 loss triggers dependence on ESRRG in retinoblastoma
| PRJNA821593 | ENA
Project description:RB1 loss triggers dependence on ESRRG in retinoblastoma
| PRJNA804875 | ENA
Project description:MYCNOS (MYCN opposite strand) is co-amplified with MYCN in pediatric cancers including retinoblastoma. MYCNOS encodes several RNA variants whose functions have not been elucidated in retinoblastoma. Here, we attempted to decipher the role of MYCNOS variant 1 (MYCNOS1) on the activity of MYCN-amplified retinoblastoma. We observed that MYCNOS1 supports progression of retinoblastoma. Inhibition of MYCNOS1 expression may be needed to suppress MYCN activity when treating MYCN-amplified cancers without RB1 mutation.
2020-12-15 | GSE161449 | GEO
Project description:Retinoblastoma (Rb) is a deadly childhood eye cancer that is classically initiated by inactivation of the RB1 tumor suppressor. Clinical management continues to rely on nonspecific chemotherapeutic agents that are associated with treatment resistance and toxicity. Here, we analyzed 103 whole exomes, 16 whole transcriptomes, 5 single-cell transcriptomes, and 4 whole genomes from primary Rb tumors to identify novel Rb dependencies. Several recurrent genomic aberrations implicate estrogen-related receptor gamma (ESRRG) in Rb pathogenesis. RB1 directly interacts with and inhibits ESRRG, and RB1 loss uncouples ESRRG from negative regulation. ESRRG regulates genes involved in retinogenesis and oxygen metabolism in Rb cells. ESRRG is preferentially expressed in hypoxic Rb cells in vivo. Depletion or inhibition of ESRRG causes marked Rb cell death which is exacerbated in hypoxia. These findings reveal a novel dependency of Rb cells on ESRRG, and they implicate ESRRG as a potential therapeutic vulnerability in Rb.
2022-08-24 | GSE196420 | GEO
Project description:In this study, we generated a human genome-wide map of DNA lesions induced by ultraviolet (UV) radiation in retinoblastoma knockout (RB1 KO) cells. Interestingly, we observed increased carcinogen susceptibility in closed HI-C domainS, pericentric and subtelomeric regions in RB1 KO. We also observed increased susceptibility at cancer driver loci such as TERT and TPTE. These loci are highly mutated in melanoma. Finally, we proposed that loss of tumor suppressor function can alter carcinogen susceptibility, and subsequently the mutation frequency of the genome.
2021-12-29 | GSE173126 | GEO
Project description:Retinoblastoma is a childhood cancer of the developing retina that initiates with biallelic inactivation of the RB1 gene. To develop a laboratory model of human retinoblastoma formation, we made induced pluripotent stem cells (iPSCs) from 15 participants with germline RB1 mutations. After 45 days in culture, the retinal organoids were dissociated and injected into the vitreous of eyes of immunocompromised mice to support retinoblastoma tumor growth. Retinoblastomas formed from retinal organoids made from patient-derived iPSCs had molecular, cellular and genomic features indistinguishable from human retinoblastomas.
2021-05-11 | GSE174201 | GEO