Abstract
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.
Highlights
The Notch pathway is a conserved developmental signaling pathway that coordinates essential cellular processes in metazoans such as differentiation, pattern formation, cell-cycle progression, morphogenesis, migration, and apoptosis
Once a mature egg is released into the oviduct, the follicle cell layer remains in the ovary as a corpus luteum [23,24]
We established a system for the investigation of ectopic Notch Intracellular Domain (NICD) accumulation in tumor cell nuclei, in vivo, using adult Drosophila follicular epithelium in an l(2)gl KD
Summary
The Notch pathway is a conserved developmental signaling pathway that coordinates essential cellular processes in metazoans such as differentiation, pattern formation, cell-cycle progression, morphogenesis, migration, and apoptosis. Canonical Notch signaling occurs at the cellular membrane of a signal-receiving cell upon direct contact with a signal-sending cell through the binding of Delta/Serrate/LAG-2 (DSL) ligand to the trans-membrane Notch (N) receptor [1]. ADAM protease cleaves the extracellular domain (NECD), forming the intermediary, membrane-tethered Notch Extracellular Truncation () [2]. In a second cleavage by γ-secretase, the active receptor Notch Intracellular Domain (NICD) is released. NICD is transported to the nucleus through the endocytosis pathway where it creates a complex with the DNA binding protein, Suppressor of Hairless (Su(H)), and the coactivator, Mastermind (Mam) and regulates downstream targets [3,4]. NICD, like other short-lived proteins, has a rich in proline (P), glutamic acid (E), serine (S) and threonine (T)
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