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

Research output: Contribution to journalArticlepeer-review

81 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 languageEnglish (US)
Pages (from-to)260-275
Number of pages16
JournalCancer Cell
Volume20
Issue number2
DOIs
StatePublished - Aug 16 2011

Bibliographical 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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