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

被引：250

作者：

Park, Jung Wook ^{[1
]}

Lee, John K. ^{[2
]}

Sheu, Katherine M. ^{[3
]}

Wang, Liang ^{[1
]}

Balanis, Nikolas G. ^{[3
]}

Kim Nguyen ^{[4
]}

Smith, Bryan A. ^{[1
]}

Cheng, Chen ^{[5
]}

Tsai, Brandon L. ^{[1
]}

Cheng, Donghui ^{[1
]}

Huang, Jiaoti ^{[6
]}

Kurdistani, Siavash K. ^{[5
,7
,8
,9
]}

Graeber, Thomas G. ^{[3
,7
,8
,9
,10
]}

Witte, Owen N. ^{[1
,3
,7
,8
,9
]}

机构：

[1] Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90095 USA

[2] Univ Calif Los Angeles, Div Hematol & Oncol, Dept Med, Los Angeles, CA 90095 USA

[3] Univ Calif Los Angeles, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA

[4] Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90095 USA

[5] Univ Calif Los Angeles, Dept Biol Chem, Los Angeles, CA 90095 USA

[6] Duke Univ, Sch Med, Dept Pathol, Durham, NC 27710 USA

[7] Univ Calif Los Angeles, Mol Biol Inst, Los Angeles, CA 90095 USA

[8] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA

[9] Univ Calif Los Angeles, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, Los Angeles, CA 90095 USA

[10] Univ Calif Los Angeles, Crump Inst Mol Imaging, Los Angeles, CA 90095 USA

来源：

SCIENCE | 2018年 / 362卷 / 6410期

基金：

美国国家卫生研究院;

关键词：

SMALL-CELL CARCINOMA; PROSTATE-CANCER; TRANSCRIPTION FACTORS; RB LOSS; EVOLUTION; DIFFERENTIATION; PLASTICITY; RESISTANCE; BCL-2;

D O I：

10.1126/science.aat5749

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：91 / 95

页数：5

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