Modeling Notch-Induced Tumor Cell Survival in the Drosophila Ovary Identifies Cellular and Transcriptional Response to Nuclear NICD Accumulation.
Modeling Notch-Induced Tumor Cell Survival in the Drosophila Ovary Identifies Cellular and Transcriptional Response to Nuclear NICD Accumulation.
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DOI：
10.3390/cells10092222
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发表时间：
2021-08-27
期刊：
影响因子：
6
通讯作者：
Deng WM
中科院分区：
文献类型：
--
作者：
Jevitt A;Huang YC;Zhang SM;Chatterjee D;Wang XF;Xie GQ;Deng WM
Notch是一种保守的发育信号通路，在许多癌症类型中失调，最常见的是通过组成性激活。具有活性Notch受体（NICD）的核积累的肿瘤细胞通常表现出增强的存活率，而患者经历较差的结果。为了了解肿瘤发生过程中NICD积累的影响，我们使用果蝇卵巢滤泡上皮开发了一种肿瘤模型。使用这个系统，我们证明了NICD积累有助于更大的肿瘤生长，减少细胞凋亡，增加核大小，减少DNA损伤的事件，而不改变倍性。使用批量RNA测序，我们确定了参与肿瘤前和肿瘤后对NICD积累的反应的关键基因。其中包括参与调节双链断裂修复、染色体组织、代谢的基因，如raptor，我们实验验证了这些基因有助于早期Notch诱导的肿瘤生长。最后，使用单细胞RNA测序，我们在NICD过表达细胞中鉴定了毛囊细胞特异性靶点，这些靶点有助于DNA修复和细胞凋亡的负调节。这个有价值的肿瘤模型，核NICD积累在成年果蝇滤泡细胞，使我们能够更好地了解具体的贡献，核NICD积累的细胞存活在肿瘤发生和肿瘤进展。
Notch is a conserved developmental signaling pathway that is dysregulated in many cancer types, most often through constitutive activation. Tumor cells with nuclear accumulation of the active Notch receptor, NICD, generally exhibit enhanced survival while patients experience poorer outcomes. To understand the impact of NICD accumulation during tumorigenesis, we developed a tumor model using the Drosophila ovarian follicular epithelium. Using this system we demonstrated that NICD accumulation contributed to larger tumor growth, reduced apoptosis, increased nuclear size, and fewer incidents of DNA damage without altering ploidy. Using bulk RNA sequencing we identified key genes involved in both a pre- and post- tumor response to NICD accumulation. Among these are genes involved in regulating double-strand break repair, chromosome organization, metabolism, like raptor, which we experimentally validated contributes to early Notch-induced tumor growth. Finally, using single-cell RNA sequencing we identified follicle cell-specific targets in NICD-overexpressing cells which contribute to DNA repair and negative regulation of apoptosis. This valuable tumor model for nuclear NICD accumulation in adult Drosophila follicle cells has allowed us to better understand the specific contribution of nuclear NICD accumulation to cell survival in tumorigenesis and tumor progression.
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影响因子：
--
作者：
Denais C;Lammerding J
通讯作者：
Lammerding J
影响因子：
8
作者：
Grifoni, D;Garoia, F;Strand, D
通讯作者：
Strand, D
果蝇卵巢滤泡上皮形态发生过程中Lgl对细胞分化和运动的要求
影响因子：
1.2
作者：
Li, Qi;Feng, Shiyun;Li, Mingfa
通讯作者：
Li, Mingfa
DOI：
10.1073/pnas.1614383114
发表时间：
2017-01-24
影响因子：
11.1
作者：
Knapp, Elizabeth;Sun, Jianjun
通讯作者：
Sun, Jianjun
DOI：
10.1126/stke.2202004pl6
发表时间：
2004-02-12
期刊：
Science's STKE : signal transduction knowledge environment
影响因子：
--
作者：
McGuire, Sean E;Mao, Zhengmei;Davis, Ronald L
通讯作者：
Davis, Ronald L