ASCL1 and NEUROD1 Reveal Heterogeneity in Pulmonary Neuroendocrine Tumors and Regulate Distinct Genetic Programs

被引：411

作者：

Borromeo, Mark D. ^{[1
]}

Savage, Trisha K. ^{[1
]}

Kollipara, Rahul K. ^{[2
]}

He, Min ^{[3
]}

Augustyn, Alexander ^{[4
]}

Osborne, Jihan K. ^{[3
]}

Girard, Luc ^{[3
,4
,5
]}

Minna, John D. ^{[3
,4
,5
,6
]}

Gazdar, Adi F. ^{[4
,5
,7
]}

Cobb, Melanie H. ^{[3
,5
]}

Johnson, Jane E. ^{[1
,3
,5
]}

机构：

[1] Univ Texas SW Med Ctr Dallas, Dept Neurosci, Dallas, TX 75390 USA

[2] Univ Texas SW Med Ctr Dallas, McDermott Ctr Human Growth & Dev, Dallas, TX 75390 USA

[3] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA

[4] Univ Texas SW Med Ctr Dallas, Hamon Ctr Therapeut Oncol Res, Dallas, TX 75390 USA

[5] Univ Texas SW Med Ctr Dallas, Simmons Comprehens Canc Ctr, Dallas, TX 75390 USA

[6] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA

[7] Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA

来源：

CELL REPORTS | 2016年 / 16卷 / 05期

关键词：

CELL LUNG-CANCER; TRANSCRIPTION FACTORS; SUPER-ENHANCERS; DIFFERENTIATION; EXPRESSION; LINES; INACTIVATION; BHLH; IDENTIFICATION; AMPLIFICATION;

D O I：

10.1016/j.celrep.2016.06.081

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

Small cell lung carcinoma (SCLC) is a high-grade pulmonary neuroendocrine tumor. The transcription factors ASCL1 and NEUROD1 play crucial roles in promoting malignant behavior and survival of human SCLC cell lines. Here, we find that ASCL1 and NEUROD1 identify heterogeneity in SCLC, bind distinct genomic loci, and regulate mostly distinct genes. ASCL1, but not NEUROD1, is present in mouse pulmonary neuroendocrine cells, and only ASCL1 is required in vivo for tumor formation in mouse models of SCLC. ASCL1 targets oncogenic genes including MYCL1, RET, SOX2, and NFIB while NEUROD1 targets MYC. ASCL1 and NEUROD1 regulate different genes that commonly contribute to neuronal function. ASCL1 also regulates multiple genes in the NOTCH pathway including DLL3. Together, ASCL1 and NEUROD1 distinguish heterogeneity in SCLC with distinct genomic landscapes and distinct gene expression programs.

引用

页码：1259 / 1272

页数：14

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