Project description:It is widely believed that the molecular and cellular features of a tumor reflect its cell-of-origin and can thus provide clues about treatment targets. The retinoblastoma cell-of-origin has been debated for over a century. Here we report that human and mouse retinoblastomas have molecular, cellular, and neurochemical features of multiple cell classes, principally amacrine/horizontal interneurons, retinal progenitor cells, and photoreceptors. Importantly, single-cell gene expression array analysis showed that these multiple cell type–specific developmental programs are coexpressed in individual retinoblastoma cells, which creates a progenitor/neuronal hybrid cell. Importantly, neurotransmitter receptors, transporters, and biosynthetic enzymes are expressed in human retinoblastoma, and targeted disruption of these pathways reduces retinoblastoma growth in vivo and in vitro. Our finding that retinoblastoma tumor cells express multiple neuronal differentiation programs that are normally incompatible in development suggests that the pathways that control retinal development and establish distinct cell types are perturbed during tumorigenesis. Therefore, the cell-of-origin for retinoblastoma cannot be inferred from the features of the tumor cells themselves. However, we now have a detailed understanding of the neuronal pathways that are deregulated in retinoblastoma and targeting the catecholamine and indolamine receptors or downstream components could provide useful therapeutic approaches in future studies. This example highlights the importance of comprehensive molecular, cellular and physiological characterization of human cancers with single cell resolution as we incorporate molecular targeted therapy into treatment regimens. 20 single cells isolated from primary pediatric retinoblastoma tumors were assayed to asses the within tumor consistency of expression signals
Project description:It is widely believed that the molecular and cellular features of a tumor reflect its cell-of-origin and can thus provide clues about treatment targets. The retinoblastoma cell-of-origin has been debated for over a century. Here we report that human and mouse retinoblastomas have molecular, cellular, and neurochemical features of multiple cell classes, principally amacrine/horizontal interneurons, retinal progenitor cells, and photoreceptors. Importantly, single-cell gene expression array analysis showed that these multiple cell type–specific developmental programs are coexpressed in individual retinoblastoma cells, which creates a progenitor/neuronal hybrid cell. Importantly, neurotransmitter receptors, transporters, and biosynthetic enzymes are expressed in human retinoblastoma, and targeted disruption of these pathways reduces retinoblastoma growth in vivo and in vitro. Our finding that retinoblastoma tumor cells express multiple neuronal differentiation programs that are normally incompatible in development suggests that the pathways that control retinal development and establish distinct cell types are perturbed during tumorigenesis. Therefore, the cell-of-origin for retinoblastoma cannot be inferred from the features of the tumor cells themselves. However, we now have a detailed understanding of the neuronal pathways that are deregulated in retinoblastoma and targeting the catecholamine and indolamine receptors or downstream components could provide useful therapeutic approaches in future studies. This example highlights the importance of comprehensive molecular, cellular and physiological characterization of human cancers with single cell resolution as we incorporate molecular targeted therapy into treatment regimens. 55 primary pediatric retinoblastoma tumors were collected and assayed and compared to with 3 passaged xenografts and 4 RB cell lines
Project description:It is widely believed that the molecular and cellular features of a tumor reflect its cell-of-origin and can thus provide clues about treatment targets. The retinoblastoma cell-of-origin has been debated for over a century. Here we report that human and mouse retinoblastomas have molecular, cellular, and neurochemical features of multiple cell classes, principally amacrine/horizontal interneurons, retinal progenitor cells, and photoreceptors. Importantly, single-cell gene expression array analysis showed that these multiple cell type–specific developmental programs are coexpressed in individual retinoblastoma cells, which creates a progenitor/neuronal hybrid cell. Importantly, neurotransmitter receptors, transporters, and biosynthetic enzymes are expressed in human retinoblastoma, and targeted disruption of these pathways reduces retinoblastoma growth in vivo and in vitro. Our finding that retinoblastoma tumor cells express multiple neuronal differentiation programs that are normally incompatible in development suggests that the pathways that control retinal development and establish distinct cell types are perturbed during tumorigenesis. Therefore, the cell-of-origin for retinoblastoma cannot be inferred from the features of the tumor cells themselves. However, we now have a detailed understanding of the neuronal pathways that are deregulated in retinoblastoma and targeting the catecholamine and indolamine receptors or downstream components could provide useful therapeutic approaches in future studies. This example highlights the importance of comprehensive molecular, cellular and physiological characterization of human cancers with single cell resolution as we incorporate molecular targeted therapy into treatment regimens.
Project description:It is widely believed that the molecular and cellular features of a tumor reflect its cell-of-origin and can thus provide clues about treatment targets. The retinoblastoma cell-of-origin has been debated for over a century. Here we report that human and mouse retinoblastomas have molecular, cellular, and neurochemical features of multiple cell classes, principally amacrine/horizontal interneurons, retinal progenitor cells, and photoreceptors. Importantly, single-cell gene expression array analysis showed that these multiple cell type–specific developmental programs are coexpressed in individual retinoblastoma cells, which creates a progenitor/neuronal hybrid cell. Importantly, neurotransmitter receptors, transporters, and biosynthetic enzymes are expressed in human retinoblastoma, and targeted disruption of these pathways reduces retinoblastoma growth in vivo and in vitro. Our finding that retinoblastoma tumor cells express multiple neuronal differentiation programs that are normally incompatible in development suggests that the pathways that control retinal development and establish distinct cell types are perturbed during tumorigenesis. Therefore, the cell-of-origin for retinoblastoma cannot be inferred from the features of the tumor cells themselves. However, we now have a detailed understanding of the neuronal pathways that are deregulated in retinoblastoma and targeting the catecholamine and indolamine receptors or downstream components could provide useful therapeutic approaches in future studies. This example highlights the importance of comprehensive molecular, cellular and physiological characterization of human cancers with single cell resolution as we incorporate molecular targeted therapy into treatment regimens.
Project description:It is widely believed that the molecular and cellular features of a tumor reflect its cell-of-origin and can thus provide clues about treatment targets. The retinoblastoma cell-of-origin has been debated for over a century. Here we report that human and mouse retinoblastomas have molecular, cellular, and neurochemical features of multiple cell classes, principally amacrine/horizontal interneurons, retinal progenitor cells, and photoreceptors. Importantly, single-cell gene expression array analysis showed that these multiple cell type–specific developmental programs are coexpressed in individual retinoblastoma cells, which creates a progenitor/neuronal hybrid cell. Importantly, neurotransmitter receptors, transporters, and biosynthetic enzymes are expressed in human retinoblastoma, and targeted disruption of these pathways reduces retinoblastoma growth in vivo and in vitro. Our finding that retinoblastoma tumor cells express multiple neuronal differentiation programs that are normally incompatible in development suggests that the pathways that control retinal development and establish distinct cell types are perturbed during tumorigenesis. Therefore, the cell-of-origin for retinoblastoma cannot be inferred from the features of the tumor cells themselves. However, we now have a detailed understanding of the neuronal pathways that are deregulated in retinoblastoma and targeting the catecholamine and indolamine receptors or downstream components could provide useful therapeutic approaches in future studies. This example highlights the importance of comprehensive molecular, cellular and physiological characterization of human cancers with single cell resolution as we incorporate molecular targeted therapy into treatment regimens.
Project description:In order to identify the gene targets of frequently altered chromosomal regions in retinoblastoma, a meta-analysis of genome-wide copy number alterations studies on primary retinoblastoma tissue and retinoblastoma cell lines was performed. Published studies were complemented by copy number and gene expression analysis on primary and cell line samples of retinoblastoma. This dataset includes the gene expression data of the retinoblastoma cell lines This data set contains the gene expression (Affymetrix human genome u133 plus 2.0 PM) results for 7 unique retinoblastoma cell lines. For one of the 7 unique cell lines, 3 RNA isolations were performed and were profiled on seperate arrays, adding up to 9 unique array files. Copy number data for primary retinoblastoma (tumor and blood DNA) and retinoblastoma cell lines are available (controlled-access) at the European Genomics Archive. Gene expression data of primary retinoblastoma is available under GSE59983. The GSE59983 records represent the primary tissue gene expression data and the CN data will be deposited into a controlled-access database, probably EGA.
Project description:<p>Retinoblastoma is a pediatric cancer of the developing retina. All retinoblastomas are believed to initiate with biallelic inactivation of the RB1 gene. To identify subsequent genetic lesions in retinoblastoma, we performed whole genome sequencing of tumor and normal DNA of 4 children with retinoblastoma and one matched orthotopic xenograft. Both alleles of RB1 were inactivated in the tumor samples. 3 of the patients had sporadic retinoblastoma and one patient had inherited retinoblastoma. Overall, there were few single nucleotide changes in coding regions of the genome and some of the tumors had few chromosomal lesions. There were very few new genetic lesions in the xenograft compared to the primary tumor. These data suggest that the genome in retinoblastoma is more stable than previously believed and there are relatively few recurrent genetic lesions in known cancer pathways other than the RB1 pathway.</p>