Department of Biological Science, Florida State University, Tallahasee, FL 32306, USA.
Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA 70112, USA.
Cells. 2021 Aug 27;10(9):2222. doi: 10.3390/cells10092222.
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 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 , 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 follicle cells has allowed us to better understand the specific contribution of nuclear NICD accumulation to cell survival in tumorigenesis and tumor progression.
Notch 是一条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。具有核积累活性 Notch 受体（NICD）的肿瘤细胞通常表现出增强的存活能力，而患者则预后较差。为了了解 Notch 积累在肿瘤发生过程中的影响，我们使用卵巢滤泡上皮开发了一种肿瘤模型。使用该系统，我们证明了 NICD 积累有助于更大的肿瘤生长、减少凋亡、增加核大小和更少的 DNA 损伤事件，而不会改变倍性。使用批量 RNA 测序，我们确定了与 NICD 积累的肿瘤前和肿瘤后反应相关的关键基因。其中包括参与调节双链断裂修复、染色体组织、代谢的基因，我们通过实验验证了其对早期 Notch 诱导的肿瘤生长的贡献。最后，使用单细胞 RNA 测序，我们确定了 NICD 过表达细胞中的卵泡细胞特异性靶标，这些靶标有助于 DNA 修复和凋亡的负调控。这种用于成年卵泡细胞中核 NICD 积累的有价值的肿瘤模型使我们能够更好地理解核 NICD 积累对肿瘤发生和肿瘤进展中细胞存活的具体贡献。
