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

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.

SUBMITTER: Jevitt A

PROVIDER: S-EPMC8465586 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Modeling Notch-induced tumor cell survival in the Drosophila ovary identifies cellular and transcriptional response to nuclear NICD accumulation

Project 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 the key Notch-induced targets involved in cell survival and DNA damage repair which were alternatively regulated prior to tumor formation. Finally, using single-cell RNA sequencing we demonstrated that genes contributing to many pathways are altered following tumor formation in a cell-type-specific manner. Ectopically expressing NICD produced dysregulated expression of genes involved in cell death regulation, immune and stress response, JAK/STAT signaling, cytoskeletal binding, adhesion, polarity, and growth regulation. This valuable tumor model for nuclear NICD accumulation in adult Drosophila follicle cells has allowed us to better understand the specific role of nuclear NICD accumulation in tumor cells in tumor cell survival and tumor progression.

2021-09-19 | GSE182505 | GEO

Modeling Notch-induced tumor cell survival in the Drosophila ovary identifies cellular and transcriptional response to nuclear NICD accumulation

Project description:Modeling Notch-induced tumor cell survival in the Drosophila ovary identifies cellular and transcriptional response to nuclear NICD accumulation

| PRJNA756536 | ENA

A single-cell atlas of adult Drosophila ovary identifies transcriptional programs and somatic cell lineage regulating oogenesis.

Project description:Oogenesis is a complex developmental process that involves spatiotemporally regulated coordination between the germline and supporting, somatic cell populations. This process has been modeled extensively using the Drosophila ovary. Although different ovarian cell types have been identified through traditional means, the large-scale expression profiles underlying each cell type remain unknown. Using single-cell RNA sequencing technology, we have built a transcriptomic data set for the adult Drosophila ovary and connected tissues. Using this data set, we identified the transcriptional trajectory of the entire follicle-cell population over the course of their development from stem cells to the oogenesis-to-ovulation transition. We further identify expression patterns during essential developmental events that take place in somatic and germline cell types such as differentiation, cell-cycle switching, migration, symmetry breaking, nurse-cell engulfment, egg-shell formation, and corpus luteum signaling. Extensive experimental validation of unique expression patterns in both ovarian and nearby, nonovarian cells also led to the identification of many new cell type-and stage-specific markers. The inclusion of several nearby tissue types in this data set also led to our identification of functional convergence in expression between distantly related cell types such as the immune-related genes that were similarly expressed in immune cells (hemocytes) and ovarian somatic cells (stretched cells) during their brief phagocytic role in nurse-cell engulfment. Taken together, these findings provide new insight into the temporal regulation of genes in a cell-type specific manner during oogenesis and begin to reveal the relatedness in expression between cell and tissues types.

| S-EPMC7205450 | biostudies-literature

Insensible is a novel nuclear inhibitor of Notch activity in Drosophila.

Project description:Notch signalling regulates a wide range of developmental processes. In the Drosophila peripheral nervous system, Notch regulates a series of binary fate decisions that lead to the formation of regularly spaced sensory organs. Each sensory organ is generated by single sensory organ precursor cell (SOP) via a series of asymmetric cell divisions. Starting from a SOP-specific Cis-Regulatory Module (CRM), we identified insensible (insb), a.k.a CG6520, as a SOP/neuron-specific gene encoding a nuclear factor that inhibits Notch signalling activity. First, over-expression of Insb led to the transcriptional repression of a Notch reporter and to phenotypes associated with the inhibition of Notch. Second, while the complete loss of insb activity had no significant phenotype, it enhanced the bristle phenotype associated with reduced levels of Hairless, a nuclear protein acting as a co-repressor for Suppressor of Hairless. In conclusion, our work identified Insb as a novel SOP/neuron-specific nuclear inhibitor of Notch activity in Drosophila.

| S-EPMC4046977 | biostudies-literature

A genetic mosaic screen identifies genes modulating Notch signaling in Drosophila.

Project description:Notch signaling is conserved in most multicellular organisms and plays critical roles during animal development. The core components and major signal transduction mechanism of Notch signaling have been extensively studied. However, our understanding of how Notch signaling activity is regulated in diverse developmental processes still remains incomplete. Here, we report a genetic mosaic screen in Drosophila melanogaster that leads to identification of Notch signali ng modulators during wing development. We discovered a group of genes required for the formation of the fly wing margin, a developmental process that is strictly dependent on the balanced Notch signaling activity. These genes encode transcription factors, protein phosphatases, vacuolar ATPases and factors required for RNA transport, stability, and translation. Our data support the view that Notch signaling is controlled through a wide range of molecular processes. These results also provide foundations for further study by showing that Me31B and Wdr62 function as two novel modulators of Notch signaling activity.

| S-EPMC6147428 | biostudies-literature

Single-cell RNA sequencing of adult Drosophila ovary identifies transcriptional programs governing oogenesis

Project description:Using single-cell RNA sequencing technology, we have built a comprehensive transcriptomic dataset for the adult Drosophila ovary and connected tissues. A total of 429,855,892 reads were obtained with 28,995 mean reads per cell for the final dataset of 7,053 high-quality cells containing an overall 11,782 genes. Using this dataset, we identified the transcriptional trajectory of the entire follicle cell population over the course of their development from stem cells to the oogenesis-to-ovulation transitioning phase in the Corpus luteum. We further identify expression patterns during essential developmental events which take place in somatic and germline cell types such as differentiation, cell-cycle switching, migration, symmetry breaking, nurse cell engulfment, egg-shell formation, and corpus luteum signaling. Extensive experimental validation of unique expression patterns in both ovarian and non-ovarian cells also led to the identification of many new markers specific to cell-type and stage. The inclusion of several nearby tissue types in this dataset also led to our identification of functional convergence in expression between distantly related cell types such as the immune-related genes which were similarly expressed in immune cells (hemocytes) and ovarian somatic cells (stretched cells) during their brief phagocytic role in nurse cell engulfment. Taken together, these findings provide new insight into the temporal regulation of genes in a cell-type specific manner during oogenesis and begin to reveal the relatedness in expression between cell and tissues types.

2020-03-27 | GSE146040 | GEO

Gene deletion screen for cardiomyopathy in adult Drosophila identifies a new notch ligand.

Project description:RATIONALE:Drosophila has been recognized as a model to study human cardiac diseases. OBJECTIVE:Despite these findings, and the wealth of tools that are available to the fly community, forward genetic screens for adult heart phenotypes have been rarely performed because of the difficulty in accurately measuring cardiac function in adult Drosophila. METHODS AND RESULTS:Using optical coherence tomography to obtain real-time analysis of cardiac function in awake Drosophila, we performed a genomic deficiency screen in adult flies. Based on multiple complementary approaches, we identified CG31665 as a novel gene causing dilated cardiomyopathy. CG31665, which we name weary (wry), has structural similarities to members of the Notch family. Using cell aggregation assays and gamma-secretase inhibitors we show that Wry is a novel Notch ligand that can mediate cellular adhesion with Notch expressing cells and transactivates Notch to promote signaling and nuclear transcription. Importantly, Wry lacks a DSL (Delta-Serrate-Lag) domain that is common feature to the other Drosophila Notch ligands. We further show that Notch signaling is critically important for the maintenance of normal heart function of the adult fly. CONCLUSIONS:In conclusion, we identify a previously unknown Notch ligand in Drosophila that when deleted causes cardiomyopathy. Our study suggests that Notch signaling components may be a therapeutic target for dilated cardiomyopathy.

| S-EPMC2860286 | biostudies-literature

Integrins control epithelial stem cell proliferation in the <i>Drosophila</i> ovary by modulating the Notch pathway.

Project description:Cell proliferation and differentiation show a remarkable inverse relationship. The temporal coupling between cell cycle withdrawal and differentiation of stem cells (SCs) is crucial for epithelial tissue growth, homeostasis and regeneration. Proliferation vs. differentiation SC decisions are often controlled by the surrounding microenvironment, of which the basement membrane (BM; a specialized form of extracellular matrix surrounding cells and tissues), is one of its main constituents. Years of research have shown that integrin-mediated SC-BM interactions regulate many aspects of SC biology, including the proliferation-to-differentiation switch. However, these studies have also demonstrated that the SC responses to interactions with the BM are extremely diverse and depend on the cell type and state and on the repertoire of BM components and integrins involved. Here, we show that eliminating integrins from the follicle stem cells (FSCs) of the Drosophila ovary and their undifferentiated progeny increases their proliferation capacity. This results in an excess of various differentiated follicle cell types, demonstrating that cell fate determination can occur in the absence of integrins. Because these phenotypes are similar to those found in ovaries with decreased laminin levels, our results point to a role for the integrin-mediated cell-BM interactions in the control of epithelial cell division and subsequent differentiation. Finally, we show that integrins regulate proliferation by restraining the activity of the Notch/Delta pathway during early oogenesis. Our work increases our knowledge of the effects of cell-BM interactions in different SC types and should help improve our understanding of the biology of SCs and exploit their therapeutic potential.

| S-EPMC10011466 | biostudies-literature

A single-cell atlas of the developing Drosophila ovary identifies follicle stem cell progenitors.

Project description:Addressing the complexity of organogenesis at a system-wide level requires a complete understanding of adult cell types, their origin, and precursor relationships. The Drosophila ovary has been a model to study how coordinated stem cell units, germline, and somatic follicle stem cells maintain and renew an organ. However, lack of cell type-specific tools have limited our ability to study the origin of individual cell types and stem cell units. Here, we used a single-cell RNA sequencing approach to uncover all known cell types of the developing ovary, reveal transcriptional signatures, and identify cell type-specific markers for lineage tracing. Our study identifies a novel cell type corresponding to the elusive follicle stem cell precursors and predicts subtypes of known cell types. Altogether, we reveal a previously unanticipated complexity of the developing ovary and provide a comprehensive resource for the systematic analysis of ovary morphogenesis.

| S-EPMC7000915 | biostudies-literature

The transcriptional corepressor SMRTER influences both Notch and ecdysone signaling during Drosophila development.

Project description:SMRTER (SMRT-related and ecdysone receptor interacting factor) is the Drosophila homologue of the vertebrate proteins SMRT and N-CoR, and forms with them a well-conserved family of transcriptional corepressors. Molecular characterization of SMRT-family proteins in cultured cells has implicated them in a wide range of transcriptional regulatory pathways. However, little is currently known about how this conserved class of transcriptional corepressors regulates the development of particular tissues via specific pathways. In this study, through our characterization of multiple Smrter (Smr) mutant lines, mosaic analysis of a loss-of-function Smr allele, and studies of two independent Smr RNAi fly lines, we report that SMRTER is required for the development of both ovarian follicle cells and the wing. In these two tissues, SMRTER inhibits not only the ecdysone pathway, but also the Notch pathway. We differentiate SMRTER's influence on these two signaling pathways by showing that SMRTER inhibits the Notch pathway, but not the ecdysone pathway, in a spatiotemporally restricted manner. We further confirm the likely involvement of SMRTER in the Notch pathway by demonstrating a direct interaction between SMRTER and Suppressor of Hairless [Su(H)], a DNA-binding transcription factor pivotal in the Notch pathway, and the colocalization of both proteins at many chromosomal regions in salivary glands. Based on our results, we propose that SMRTER regulates the Notch pathway through its association with Su(H), and that overcoming a SMRTER-mediated transcriptional repression barrier may represent a key mechanism used by the Notch pathway to control the precise timing of events and the formation of sharp boundaries between cells in multiple tissues during development.

| S-EPMC3507286 | biostudies-literature

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