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

当前位置： X-MOL 学术 › Science › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Reprogramming normal human epithelial tissues to a common, lethal neuroendocrine cancer lineage
Science ( IF 56.9 ) Pub Date : 2018-10-04 , DOI: 10.1126/science.aat5749
Jung Wook Park ₁ , John K Lee ₂ , Katherine M Sheu ₃ , Liang Wang ₁ , Nikolas G Balanis ₃ , Kim Nguyen ₄ , Bryan A Smith ₁ , Chen Cheng ₅ , Brandon L Tsai ₁ , Donghui Cheng ₁ , Jiaoti Huang ₆ , Siavash K Kurdistani _{5,

7,

8,

9} , Thomas G Graeber _{3,

7,

8,

9,

10} , Owen N Witte _{1,

3,

7,

8,

9}

Affiliation

Department of Microbiology, Immunology, and Molecular Genetics, University of California-Los Angeles, Los Angeles, CA 90095, USA.
Division of Hematology and Oncology, Department of Medicine, University of California-Los Angeles, Los Angeles, CA 90095, USA.
Department of Molecular and Medical Pharmacology, University of California-Los Angeles, Los Angeles, CA 90095, USA.
Department of Ecology and Evolutionary Biology, University of California-Los Angeles, Los Angeles, CA 90095, USA.
Department of Biological Chemistry, University of California-Los Angeles, Los Angeles, CA 90095, USA.
Department of Pathology, School of Medicine, Duke University, Durham, NC 27710, USA.
Molecular Biology Institute, University of California-Los Angeles, Los Angeles, CA 90095, USA.
Jonsson Comprehensive Cancer Center, University of California-Los Angeles, Los Angeles, CA 90095, USA.
Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California-Los Angeles, Los Angeles, CA 90095, USA.
Crump Institute for Molecular Imaging, University of California-Los Angeles, Los Angeles, CA 90095, USA.

Some (re)programming notes on cancer Epithelial cancers develop resistance to targeted therapies in a number of different ways. Several cancer types do so by undergoing phenotypic conversion to a highly aggressive cancer called small cell neuroendocrine carcinoma (SCNC). Whether distinct cancer types accomplish this “reprogramming” through the same mechanism has been unclear. Park et al. show that the same set of oncogenic factors transforms both normal lung and normal prostate epithelial cells into SCNCs that resemble clinical samples (see the Perspective by Kareta and Sage). This convergence of molecular pathways could potentially simplify the development of new therapies for SCNC, which is currently untreatable. Science, this issue p. 91; see also p. 30 Prostate and lung cancers convert to a drug-resistant, lethal form of cancer through the same reprogramming mechanism. 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.

更新日期：2018-10-04

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文本刊介绍/投稿指南

全部期刊列表>>