scholarly journals Ionizing radiation induces stem cell-like properties in a caspase-dependent manner in Drosophila

2018 ◽  
Author(s):  
Shilpi Verghese ◽  
Tin Tin Su
Keyword(s):  
Stem Cell ◽  
Ionizing Radiation ◽  
Cancer Cells ◽  
Wing Disc ◽  
Lineage Tracing ◽  
Dependent Manner ◽  
Cancer Treatments ◽  
Therapeutic Success ◽  
Wing Discs ◽  
Regenerative Cells

ABSTRACTCancer treatments including ionizing radiation (IR) can induce cancer stem cell-like properties in non-stem cancer cells, an outcome that can interfere with therapeutic success. Yet, we understand little about what consequences of IR induces stem cell like properties and why some cancer cells show this response but not others. In previous studies, we identified a pool of epithelial cells in Drosophila larval wing discs that display IR-induced stem cell-like properties. These cells are resistant to killing by IR and, after radiation damage, change fate and translocate to regenerate parts of the disc that suffered more cell death. Here, we addressed how IR exposure results in the induction of stem cell-like behavior, and found a requirement for caspase activity. Unexpectedly, this requirement was mapped to the regenerative cells, suggesting a non-apoptotic role for caspases in the induction of stem cell-like behavior. We also performed a systematic probing of different regions of the wing disc by lineage tracing, in order to identify additional pools of cells with IR-induced regenerative properties. We identified two new populations of such cells. Unlike the original pool that helps regenerate the disc, the new pools of cells undergo abnormal regeneration to produce an ectopic, supernumerary wing disc. We also identified cells that lack the ability to display IR-induced regenerative behavior. Identification of different cell populations with different IR-induced regenerative potential will allow us to probe the molecular basis for these differences in the future.AUTHOR SUMMARYIonizing Radiation (IR), alone or in combination with other therapies, is used to treat an estimated half of all cancer patients. Yet, we understand little about why some tumors cells respond to treatment while others grow back (regenerate). We identified specific pools of cells within a Drosophila organ that are capable of regeneration after damage by IR. We also identified what it is about IR damage that allows these cells to regenerate. These results help us understand how cells regenerate after IR damage and will aid in designing better therapies that involve radiation.

scholarly journals Differential gene expression analysis identified determinants of cell fate plasticity during radiation-induced regeneration in Drosophila

PLoS Genetics ◽  
2022 ◽  
Vol 18 (1) ◽  
pp. e1009989
Author(s):  
Michelle Ledru ◽  
Caitlin A. Clark ◽  
Jeremy Brown ◽  
Shilpi Verghese ◽  
Sarah Ferrara ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Fate ◽  
Ribosome Biogenesis ◽  
Lineage Tracing ◽  
Therapeutic Success ◽  
Genome Wide ◽  
Radiation Induced ◽  
Differential Gene ◽  
Wing Discs ◽  
Induced Apoptosis

Ionizing radiation (IR) is used to treat half of all cancer patients because of its ability to kill cells. IR, however, can induce stem cell-like properties in non-stem cancer cells, potentiating tumor regrowth and reduced therapeutic success. We identified previously a subpopulation of cells in Drosophila larval wing discs that exhibit IR-induced stem cell-like properties. These cells reside in the future wing hinge, are resistant to IR-induced apoptosis, and are capable of translocating, changing fate, and participating in regenerating the pouch that suffers more IR-induced apoptosis. We used here a combination of lineage tracing, FACS-sorting of cells that change fate, genome-wide RNAseq, and functional testing of 42 genes, to identify two key changes that are required cell-autonomously for IR-induced hinge-to-pouch fate change: (1) repression of hinge determinants Wg (Drosophila Wnt1) and conserved zinc-finger transcription factor Zfh2 and (2) upregulation of three ribosome biogenesis factors. Additional data indicate a role for Myc, a transcriptional activator of ribosome biogenesis genes, in the process. These results provide a molecular understanding of IR-induced cell fate plasticity that may be leveraged to improve radiation therapy.

scholarly journals Targeted mobilization of Lrig1+ gastric epithelial stem cell populations by a carcinogenic Helicobacter pylori type IV secretion system

2019 ◽  
Vol 116 (39) ◽  
pp. 19652-19658 ◽  
Author(s):  
Lydia E. Wroblewski ◽  
Eunyoung Choi ◽  
Christine Petersen ◽  
Alberto G. Delgado ◽  
M. Blanca Piazuelo ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Stem Cell ◽  
Progenitor Cells ◽  
Intrinsic Factor ◽  
Secretion System ◽  
Lineage Tracing ◽  
Host Cells ◽  
Dependent Manner ◽  
Cell Marker ◽  
H Pylori

Helicobacter pylori-induced gastritis is the strongest risk factor for gastric adenocarcinoma, a malignancy preceded by a series of well-defined histological stages, including metaplasia. One microbial constituent that augments cancer risk is the cag type 4 secretion system (T4SS), which translocates the oncoprotein CagA into host cells. Aberrant stem cell activation is linked to carcinogenesis, and Lrig1 (leucine-rich repeats and Ig-like domains 1) marks a distinct population of progenitor cells. We investigated whether microbial effectors with carcinogenic potential influence Lrig1 progenitor cells ex vivo and via lineage expansion within H. pylori-infected gastric mucosa. Lineage tracing was induced in Lrig1-CreERT2/+;R26R-YFP/+ (Lrig1/YFP) mice that were uninfected or subsequently infected with cag+H. pylori or an isogenic cagE− mutant (nonfunctional T4SS). In contrast to infection with wild-type (WT) H. pylori for 2 wk, infection for 8 wk resulted in significantly increased inflammation and proliferation in the corpus and antrum compared with uninfected or mice infected with the cagE− mutant. WT H. pylori-infected mice harbored significantly higher numbers of Lrig1/YFP epithelial cells that coexpressed UEA1 (surface cell marker). The number of cells coexpressing intrinsic factor (chief cell marker), YFP (lineage marker), and GSII lectin (spasmolytic polypeptide-expressing metaplasia marker) were increased only by WT H. pylori. In human samples, Lrig1 expression was significantly increased in lesions with premalignant potential compared with normal mucosa or nonatrophic gastritis. In conclusion, chronic H. pylori infection stimulates Lrig1-expressing progenitor cells in a cag-dependent manner, and these reprogrammed cells give rise to a full spectrum of differentiated cells.

scholarly journals Inflammatory Human Umbilical Cord-Derived Mesenchymal Stem Cells Promote Stem Cell-Like Characteristics of Cancer Cells in an IL-1β-Dependent Manner

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Xiaohe Luo ◽  
Shan Huang ◽  
Ningning He ◽  
Chen Liu ◽  
Yanan Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Cancer Cells ◽  
Umbilical Cord ◽  
Side Population ◽  
Ovarian Cancer Cells ◽  
Human Umbilical Cord ◽  
Stem Cell Markers ◽  
Dependent Manner

To ensure the safety of clinical applications of MSCs, thorough understanding of their impacts on tumor initiation and progression is essential. Here, to further explore the complex dialog between MSCs and tumor cells, umbilical cord-derived mesenchymal stem cells (UC-MSCs) were employed to be cocultured with either breast or ovarian cancer cells. Though having no obvious influence on proliferation or apoptosis, UC-MSCs exerted intense stem cell-like properties promoting effects on both cancer models. Cocultured cancer cells showed enriched side population, enhanced sphere formation ability, and upregulated pluripotency-associated stem cell markers. Human cytokine array and real-time PCR revealed a panel of MSC-derived prostemness cytokines CCL2, CXCL1, IL-8, and IL-6 which were induced upon coculturing. We further revealed IL-1β, a well-characterized proinflammatory cytokine, to be the inducer of these prostemness cytokines, which was generated from inflammatory UC-MSCs in an autocrine manner. Additionally, with introduction of IL-1RA (an IL-1 receptor antagonist) into the coculturing system, the stem cell-like characteristics promoting effects of inflammatory UC-MSCs were partially blocked. Taken together, these findings suggest that transduced inflammatory MSCs work as a major source of IL-1β in tumor microenvironment and initiate the formation of prostemness niche via regulating their secretome in an IL-1β-dependent manner.

scholarly journals Nucleosome remodelling, DNA repair and transcriptional regulation build negative feedback loops in cancer and cellular ageing

2017 ◽  
Vol 372 (1731) ◽  
pp. 20160473 ◽  
Author(s):  
Reiko Watanabe ◽  
Shin-ichiro Kanno ◽  
Amaneh Mohammadi Roushandeh ◽  
Ayako Ui ◽  
Akira Yasui
Keyword(s):  
Dna Repair ◽  
Transcriptional Regulation ◽  
Stem Cell ◽  
Cancer Cells ◽  
Negative Feedback ◽  
Feedback Loops ◽  
Dependent Manner ◽  
Epigenetic Changes ◽  
Negative Feedback Loops ◽  
Cellular Ageing

Nucleosome remodelling (NR) regulates transcription in an ATP-dependent manner, and influences gene expression required for development and cellular functions, including those involved in anti-cancer and anti-ageing processes. ATP-utilizing chromatin assembly and remodelling factor (ACF) and Brahma-associated factor (BAF) complexes, belonging to the ISWI and SWI/SNF families, respectively, are involved in various types of DNA repair. Suppression of several BAF factors makes U2OS cells significantly sensitive to X-rays, UV and especially to cisplatin, and these BAF factors contribute to the accumulation of repair proteins at various types of DNA damage and to DNA repair. Recent cancer genome sequencing and expression analysis has shown that BAF factors are frequently mutated or, more frequently, silenced in various types of cancer cells. Thus, those cancer cells are potentially X-ray- and especially cisplatin-sensitive, suggesting a way of optimizing current cancer therapy. Recent single–stem cell analysis suggests that mutations and epigenetic changes influence stem cell functionality leading to cellular ageing. Genetic and epigenetic changes in the BAF factors diminish DNA repair as well as transcriptional regulation activities, and DNA repair defects in turn negatively influence NR and transcriptional regulation. Thus, they build negative feedback loops, which accelerate both cellular senescence and transformation as common and rare cellular events, respectively, causing cellular ageing. This article is part of the themed issue ‘Chromatin modifiers and remodellers in DNA repair and signalling’.

scholarly journals Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m6A-demethylation of NANOG mRNA

2016 ◽  
Vol 113 (14) ◽  
pp. E2047-E2056 ◽  
Author(s):  
Chuanzhao Zhang ◽  
Debangshu Samanta ◽  
Haiquan Lu ◽  
John W. Bullen ◽  
Huimin Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Embryonic Stem ◽  
Breast Cancer Stem Cell ◽  
Luciferase Reporter ◽  
Cell Phenotype ◽  
Dependent Manner

N6-methyladenosine (m6A) modification of mRNA plays a role in regulating embryonic stem cell pluripotency. However, the physiological signals that determine the balance between methylation and demethylation have not been described, nor have studies addressed the role of m6A in cancer stem cells. We report that exposure of breast cancer cells to hypoxia stimulated hypoxia-inducible factor (HIF)-1α- and HIF-2α–dependent expression of AlkB homolog 5 (ALKBH5), an m6A demethylase, which demethylated NANOG mRNA, which encodes a pluripotency factor, at an m6A residue in the 3′-UTR. Increased NANOG mRNA and protein expression, and the breast cancer stem cell (BCSC) phenotype, were induced by hypoxia in an HIF- and ALKBH5-dependent manner. Insertion of the NANOG 3′-UTR into a luciferase reporter gene led to regulation of luciferase activity by O2, HIFs, and ALKBH5, which was lost upon mutation of the methylated residue. ALKBH5 overexpression decreased NANOG mRNA methylation, increased NANOG levels, and increased the percentage of BCSCs, phenocopying the effect of hypoxia. Knockdown of ALKBH5 expression in MDA-MB-231 human breast cancer cells significantly reduced their capacity for tumor initiation as a result of reduced numbers of BCSCs. Thus, HIF-dependent ALKBH5 expression mediates enrichment of BCSCs in the hypoxic tumor microenvironment.

scholarly journals Cytonemes coordinate asymmetric signaling and organization in the Drosophila muscle progenitor niche

2021 ◽  
Author(s):  
Akshay Patel ◽  
Yicong Wu ◽  
Xiaofei Han ◽  
Yijun Su ◽  
Tim K. Maugel ◽  
...  
Keyword(s):  
Stem Cell ◽  
Wing Disc ◽  
Dependent Manner ◽  
Fgf Signaling ◽  
Cell Fates ◽  
Fgf Receptor ◽  
Drosophila Wing ◽  
Epithelial Junctions ◽  
Cell Organization ◽  
Cell Niche

Asymmetric signaling and organization in the stem-cell niche determine stem-cell fates. We investigated the basis of asymmetric signaling and stem-cell organization using the Drosophila wing-disc that creates an adult muscle progenitor (AMP) niche. We uncovered that AMPs extend polarized cytonemes to contact the disc epithelial junctions and adhere themselves to the disc/niche. Niche-adhering cytonemes localize an FGF-receptor to selectively adhere to the FGF-producing disc and receive FGFs in a contact-dependent manner. Activation of FGF-signaling in AMPs, in turn, reinforces disc-specific cytoneme polarity/adhesion, which maintains their disc-proximal positions. The wing-disc produces two FGFs in distinct zones and restricts their signaling only through cytonemes. Consequently, although both FGFs use the same receptor, their cytoneme-mediated signaling asymmetrically distributes different muscle-specific AMPs into different FGF-producing niches. Loss of cytoneme-mediated adhesion and FGF-signaling promotes AMPs to lose niche occupancy, occupy a disc-distal position, and acquire morphological hallmarks of differentiation. Thus, cytonemes are essential for asymmetric signaling and niche-specific AMP organization.

scholarly journals In vivo relevance of intercellular calcium signaling in Drosophila wing development

2017 ◽  
Author(s):  
Qinfeng Wu ◽  
Pavel A. Brodskiy ◽  
Francisco Huizar ◽  
Jamison J. Jangula ◽  
Cody Narciso ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Wing Disc ◽  
Chemical Stimulus ◽  
Wing Development ◽  
Dependent Manner ◽  
Drosophila Wing ◽  
Wing Discs ◽  
Vein Patterning ◽  
Dose Dependent

AbstractRecently, organ-scale intercellular Ca2+ transients (ICTs) were reported in the Drosophila wing disc. However, the functional in vivo significance of ICTs remains largely unknown. Here we demonstrate the in vivo relevance of intercellular Ca2+ signaling and its impact on wing development. We report that Ca2+ signaling in vivo decreases as wing discs mature. Ca2+ signaling ex vivo responds to fly extract in a dose-dependent manner. This suggests ICTs occur in vivo due to chemical stimulus that varies in concentration during development. RNAi mediated inhibition of genes required for ICTs results in defects in the size, shape, and vein patterning of adult wings. It also leads to reduction or elimination of in vivo Ca2+ transients. Further, perturbations to the extracellular matrix along the basal side of the wing disc stimulates intercellular Ca2+ waves. This is the first identified chemically defined, non-wounding stimulus of ICTs. Together, these results point toward specific in vivo functions of intercellular Ca2+ signaling to mediate mechanical stress dissipation and ensure robust patterning during development.

scholarly journals Bab2 activates JNK signaling to reprogram Drosophila wing disc development

2020 ◽  
Author(s):  
Yunpo Zhao ◽  
Jianli Duan ◽  
Alexis Dziedziech ◽  
Sabrina Büttner ◽  
Ylva Engström
Keyword(s):  
Transcription Factor ◽  
Cellular Proliferation ◽  
Apoptotic Cell ◽  
Wing Disc ◽  
Surrounding Tissue ◽  
Dependent Manner ◽  
Posterior Compartment ◽  
Jnk Signaling ◽  
Compensatory Proliferation ◽  
Wing Discs

AbstractIn response to cellular stress and damage, certain tissues are able to regenerate and to restore tissue homeostasis. In Drosophila imaginal wing discs, dying cells express mitogens that induce compensatory proliferation in the surrounding tissue. Here we report that high levels of the BTB/POZ transcription factor Bab2 in the posterior compartment of wing discs activates c-Jun N-terminal kinase (JNK) signaling and local, cell-autonomous apoptotic cell death. This in turn triggered the upregulation of the Dpp mitogen and cellular proliferation in the anterior compartment in a JNK-dependent manner. In the posterior compartment, however, dpp expression was suppressed, most likely by direct transcriptional repression by Bab2. This dual-mode of JNK-signaling, autocrine pro-apoptotic signaling and paracrine pro-proliferative signaling, led to opposite effects in the two compartments and reprogramming of the adult wing structure. We establish Bab2 as a regulator of wing disc development, with the capacity to reprogram development via JNK activation in a cell-autonomous and non-cell-autonomous manner.Summary statementZhao et al. shows that the BTB/POZ transcription factor Bab2 is a potent activator of JNK signaling, apoptosis and compensatory proliferation, thereby driving both pro-tumorigenic and anti-tumorigenic processes.

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