ASCL1 and NEUROD1 Reveal Heterogeneity in Pulmonary Neuroendocrine Tumors and Regulate Distinct Genetic Programs.
ASCL1 and NEUROD1 Reveal Heterogeneity in Pulmonary Neuroendocrine Tumors and Regulate Distinct Genetic Programs.
复制标题
DOI：
10.1016/j.celrep.2016.06.081
复制
发表时间：
2016-08-02
期刊：
影响因子：
8.8
通讯作者：
Johnson JE
中科院分区：
文献类型：
--
作者：
Borromeo MD;Savage TK;Kollipara RK;He M;Augustyn A;Osborne JK;Girard L;Minna JD;Gazdar AF;Cobb MH;Johnson JE
小细胞肺癌（SCLC）是一种高度恶性的肺神经内分泌肿瘤。转录因子ASCL1和NEUROD1在促进人SCLC细胞系的恶性行为和存活中起关键作用。我们发现ASCL1和NEUROD1识别SCLC的异质性，结合不同的基因组位点，并调节大多数不同的基因。小鼠肺神经内分泌细胞中存在ASCL1，而非NEUROD1，并且在SCLC小鼠模型中，体内肿瘤形成仅需要ASCL1。ASCL1靶向致癌基因，包括MYCL1、RET、SOX 2和NFIB，而NEUROD1靶向MYC。ASCL1和NEUROD1调节通常有助于神经元功能的不同基因。ASCL1还调节NOTCH途径中的多个基因，包括DLL3。ASCL1和NEUROD1共同区分SCLC的异质性，具有不同的基因组景观和不同的基因表达程序。
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. We find 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.