Coexpression of Normally Incompatible Developmental Pathways in Retinoblastoma Genesis

Justina McEvoy; Jacqueline Flores-Otero; Jiakun Zhang; Katie Nemeth; Rachel Brennan; Cori Bradley; Fred Krafcik; Carlos Rodriguez-Galindo; Matthew Wilson; Shunbin Xiong; Guillermina Lozano; Julien Sage; Ligia Fu; Lotfi Louhibi; Jeff Trimarchi; Amar Pani; Richard Smeyne; Dianna Johnson; Michael A. Dyer

doi:10.1016/j.ccr.2011.07.005

Coexpression of Normally Incompatible Developmental Pathways in Retinoblastoma Genesis

Justina McEvoy, Jacqueline Flores-Otero, Jiakun Zhang, Katie Nemeth, Rachel Brennan, Cori Bradley, Fred Krafcik, Carlos Rodriguez-Galindo, Matthew Wilson, Shunbin Xiong, Guillermina Lozano, Julien Sage, Ligia Fu, Lotfi Louhibi, Jeff Trimarchi, Amar Pani, Richard Smeyne, Dianna Johnson, Michael A. Dyer

Genetics

Research output: Contribution to journal › Article › peer-review

106 Scopus citations

Abstract

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. Furthermore, 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.

Original language	English (US)
Pages (from-to)	260-275
Number of pages	16
Journal	Cancer cell
Volume	20
Issue number	2
DOIs	https://doi.org/10.1016/j.ccr.2011.07.005
State	Published - Aug 16 2011

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

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McEvoy, J., Flores-Otero, J., Zhang, J., Nemeth, K., Brennan, R., Bradley, C., Krafcik, F., Rodriguez-Galindo, C., Wilson, M., Xiong, S., Lozano, G., Sage, J., Fu, L., Louhibi, L., Trimarchi, J., Pani, A., Smeyne, R., Johnson, D., & Dyer, M. A. (2011). Coexpression of Normally Incompatible Developmental Pathways in Retinoblastoma Genesis. Cancer cell, 20(2), 260-275. https://doi.org/10.1016/j.ccr.2011.07.005

McEvoy, J, Flores-Otero, J, Zhang, J, Nemeth, K, Brennan, R, Bradley, C, Krafcik, F, Rodriguez-Galindo, C, Wilson, M, Xiong, S , Lozano, G, Sage, J, Fu, L, Louhibi, L, Trimarchi, J, Pani, A, Smeyne, R, Johnson, D & Dyer, MA 2011, 'Coexpression of Normally Incompatible Developmental Pathways in Retinoblastoma Genesis', Cancer cell, vol. 20, no. 2, pp. 260-275. https://doi.org/10.1016/j.ccr.2011.07.005

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title = "Coexpression of Normally Incompatible Developmental Pathways in Retinoblastoma Genesis",

abstract = "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. Furthermore, 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.",

author = "Justina McEvoy and Jacqueline Flores-Otero and Jiakun Zhang and Katie Nemeth and Rachel Brennan and Cori Bradley and Fred Krafcik and Carlos Rodriguez-Galindo and Matthew Wilson and Shunbin Xiong and Guillermina Lozano and Julien Sage and Ligia Fu and Lotfi Louhibi and Jeff Trimarchi and Amar Pani and Richard Smeyne and Dianna Johnson and Dyer, {Michael A.}",

note = "Funding Information: We thank Kip Guy and Anang Shelat for assistance with high-throughput screening and cheminformatics; Sharon Frase and Marina Kedrov for assistance with electron microscopy and morphometric scoring; Geoff Neale for assistance with bioinformatics, Connie Cepko for sharing data, methods, and reagents and for many helpful discussions; David Cobrinik for providing the MSKCC176 cells and for helpful discussions; Justin Thurman for assistance with the animal colony and sectioning; Angela McArthur for editing the manuscript; and Wei Zhao for assistance with biostatistics. This work was supported in part by Cancer Center Support (CA21765) from the NCI; grants to M.A.D from the NIH (EY014867 and EY018599), the American Cancer Society, and Research to Prevent Blindness Foundation; a grant to J.S. (CA114102); and the American Lebanese Syrian Associated Charities (ALSAC). M.A.D. is a Howard Hughes Medical Institute Early Career Scientist. ",

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AU - McEvoy, Justina

AU - Flores-Otero, Jacqueline

AU - Zhang, Jiakun

AU - Nemeth, Katie

AU - Brennan, Rachel

AU - Bradley, Cori

AU - Krafcik, Fred

AU - Rodriguez-Galindo, Carlos

AU - Wilson, Matthew

AU - Xiong, Shunbin

AU - Lozano, Guillermina

AU - Sage, Julien

AU - Fu, Ligia

AU - Louhibi, Lotfi

AU - Trimarchi, Jeff

AU - Pani, Amar

AU - Smeyne, Richard

AU - Johnson, Dianna

AU - Dyer, Michael A.

N1 - Funding Information: We thank Kip Guy and Anang Shelat for assistance with high-throughput screening and cheminformatics; Sharon Frase and Marina Kedrov for assistance with electron microscopy and morphometric scoring; Geoff Neale for assistance with bioinformatics, Connie Cepko for sharing data, methods, and reagents and for many helpful discussions; David Cobrinik for providing the MSKCC176 cells and for helpful discussions; Justin Thurman for assistance with the animal colony and sectioning; Angela McArthur for editing the manuscript; and Wei Zhao for assistance with biostatistics. This work was supported in part by Cancer Center Support (CA21765) from the NCI; grants to M.A.D from the NIH (EY014867 and EY018599), the American Cancer Society, and Research to Prevent Blindness Foundation; a grant to J.S. (CA114102); and the American Lebanese Syrian Associated Charities (ALSAC). M.A.D. is a Howard Hughes Medical Institute Early Career Scientist.

PY - 2011/8/16

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N2 - 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. Furthermore, 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.

AB - 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. Furthermore, 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.

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Coexpression of Normally Incompatible Developmental Pathways in Retinoblastoma Genesis

Abstract

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