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Science. 2018 Oct 5;362(6410):91-95. doi: 10.1126/science.aat5749.

Reprogramming normal human epithelial tissues to a common, lethal neuroendocrine cancer lineage.

Author information

1
Department of Microbiology, Immunology, and Molecular Genetics, University of California-Los Angeles, Los Angeles, CA 90095, USA.
2
Division of Hematology and Oncology, Department of Medicine, University of California-Los Angeles, Los Angeles, CA 90095, USA.
3
Department of Molecular and Medical Pharmacology, University of California-Los Angeles, Los Angeles, CA 90095, USA.
4
Department of Ecology and Evolutionary Biology, University of California-Los Angeles, Los Angeles, CA 90095, USA.
5
Department of Biological Chemistry, University of California-Los Angeles, Los Angeles, CA 90095, USA.
6
Department of Pathology, School of Medicine, Duke University, Durham, NC 27710, USA.
7
Molecular Biology Institute, University of California-Los Angeles, Los Angeles, CA 90095, USA.
8
Jonsson Comprehensive Cancer Center, University of California-Los Angeles, Los Angeles, CA 90095, USA.
9
Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California-Los Angeles, Los Angeles, CA 90095, USA.
10
Department of Molecular and Medical Pharmacology, University of California-Los Angeles, Los Angeles, CA 90095, USA. owenwitte@mednet.ucla.edu tgraeber@mednet.ucla.edu.
11
Crump Institute for Molecular Imaging, University of California-Los Angeles, Los Angeles, CA 90095, USA.
12
Department of Microbiology, Immunology, and Molecular Genetics, University of California-Los Angeles, Los Angeles, CA 90095, USA. owenwitte@mednet.ucla.edu tgraeber@mednet.ucla.edu.

Abstract

The use of potent therapies inhibiting critical oncogenic pathways active in epithelial cancers has led to multiple resistance mechanisms, including the development of highly aggressive, small cell neuroendocrine carcinoma (SCNC). SCNC patients have a dismal prognosis due in part to a limited understanding of the molecular mechanisms driving this malignancy and the lack of effective treatments. Here, we demonstrate that a common set of defined oncogenic drivers reproducibly reprograms normal human prostate and lung epithelial cells to small cell prostate cancer (SCPC) and small cell lung cancer (SCLC), respectively. We identify shared active transcription factor binding regions in the reprogrammed prostate and lung SCNCs by integrative analyses of epigenetic and transcriptional landscapes. These results suggest that neuroendocrine cancers arising from distinct epithelial tissues may share common vulnerabilities that could be exploited for the development of drugs targeting SCNCs.

PMID:
30287662
DOI:
10.1126/science.aat5749

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