Cargando…

Modeling Notch-Induced Tumor Cell Survival in the Drosophila Ovary Identifies Cellular and Transcriptional Response to Nuclear NICD Accumulation

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 unde...

Descripción completa

Detalles Bibliográficos
Autores principales: Jevitt, Allison, Huang, Yi-Chun, Zhang, Su-Mei, Chatterjee, Deeptiman, Wang, Xian-Feng, Xie, Geng-Qiang, Deng, Wu-Min
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8465586/
https://www.ncbi.nlm.nih.gov/pubmed/34571871
http://dx.doi.org/10.3390/cells10092222
_version_ 1784572913692704768
author Jevitt, Allison
Huang, Yi-Chun
Zhang, Su-Mei
Chatterjee, Deeptiman
Wang, Xian-Feng
Xie, Geng-Qiang
Deng, Wu-Min
author_facet Jevitt, Allison
Huang, Yi-Chun
Zhang, Su-Mei
Chatterjee, Deeptiman
Wang, Xian-Feng
Xie, Geng-Qiang
Deng, Wu-Min
author_sort Jevitt, Allison
collection PubMed
description 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.
format Online
Article
Text
id pubmed-8465586
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-84655862021-09-27 Modeling Notch-Induced Tumor Cell Survival in the Drosophila Ovary Identifies Cellular and Transcriptional Response to Nuclear NICD Accumulation Jevitt, Allison Huang, Yi-Chun Zhang, Su-Mei Chatterjee, Deeptiman Wang, Xian-Feng Xie, Geng-Qiang Deng, Wu-Min Cells Article 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. MDPI 2021-08-27 /pmc/articles/PMC8465586/ /pubmed/34571871 http://dx.doi.org/10.3390/cells10092222 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Jevitt, Allison
Huang, Yi-Chun
Zhang, Su-Mei
Chatterjee, Deeptiman
Wang, Xian-Feng
Xie, Geng-Qiang
Deng, Wu-Min
Modeling Notch-Induced Tumor Cell Survival in the Drosophila Ovary Identifies Cellular and Transcriptional Response to Nuclear NICD Accumulation
title Modeling Notch-Induced Tumor Cell Survival in the Drosophila Ovary Identifies Cellular and Transcriptional Response to Nuclear NICD Accumulation
title_full Modeling Notch-Induced Tumor Cell Survival in the Drosophila Ovary Identifies Cellular and Transcriptional Response to Nuclear NICD Accumulation
title_fullStr Modeling Notch-Induced Tumor Cell Survival in the Drosophila Ovary Identifies Cellular and Transcriptional Response to Nuclear NICD Accumulation
title_full_unstemmed Modeling Notch-Induced Tumor Cell Survival in the Drosophila Ovary Identifies Cellular and Transcriptional Response to Nuclear NICD Accumulation
title_short Modeling Notch-Induced Tumor Cell Survival in the Drosophila Ovary Identifies Cellular and Transcriptional Response to Nuclear NICD Accumulation
title_sort modeling notch-induced tumor cell survival in the drosophila ovary identifies cellular and transcriptional response to nuclear nicd accumulation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8465586/
https://www.ncbi.nlm.nih.gov/pubmed/34571871
http://dx.doi.org/10.3390/cells10092222
work_keys_str_mv AT jevittallison modelingnotchinducedtumorcellsurvivalinthedrosophilaovaryidentifiescellularandtranscriptionalresponsetonuclearnicdaccumulation
AT huangyichun modelingnotchinducedtumorcellsurvivalinthedrosophilaovaryidentifiescellularandtranscriptionalresponsetonuclearnicdaccumulation
AT zhangsumei modelingnotchinducedtumorcellsurvivalinthedrosophilaovaryidentifiescellularandtranscriptionalresponsetonuclearnicdaccumulation
AT chatterjeedeeptiman modelingnotchinducedtumorcellsurvivalinthedrosophilaovaryidentifiescellularandtranscriptionalresponsetonuclearnicdaccumulation
AT wangxianfeng modelingnotchinducedtumorcellsurvivalinthedrosophilaovaryidentifiescellularandtranscriptionalresponsetonuclearnicdaccumulation
AT xiegengqiang modelingnotchinducedtumorcellsurvivalinthedrosophilaovaryidentifiescellularandtranscriptionalresponsetonuclearnicdaccumulation
AT dengwumin modelingnotchinducedtumorcellsurvivalinthedrosophilaovaryidentifiescellularandtranscriptionalresponsetonuclearnicdaccumulation