DNA Damage Induces a Secretory Program in the Quiescent Tumor Microenvironment that Promotes Adverse Prostate Cancer Phenotypes
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE92853 | GEO | 2017/11/16
SECONDARY ACCESSION(S): PRJNA358617
REPOSITORIES: GEO
Similar Datasets
Project description:Carcinomas develop in complex environments that include a diverse spectrum of cell types that influence tumor cell behavior. These microenvironments represent dynamic systems that contribute to pathologic processes. Damage to DNA is a notable inducer of both transient and permanent alterations in cellular phenotypes. Induction of a DNA damage secretory program is known to promote adverse tumor cell behaviors such as proliferation, invasion, metastasis, and treatment resistance. However, prior studies designed to identify genotoxic stress-induced factors evaluated actively proliferating in vitro cultures of cells such as fibroblasts as experimental models. Conversely, the vast majority of benign cells in a typical tumor microenvironment (TME) are not proliferating but rather exist in quiescent (i.e., G0) or in terminally differentiated states. In this study, the diversity and magnitude of transcriptional responses to genotoxic damage in quiescent prostate fibroblasts were assessed using gene expression profiling. The secretory damage response in quiescent cells was highly concordant with that of actively dividing cells. Quiescent human prostate stroma exposed to genotoxic agents (e.g., mitoxantrone) in vivo resulted in significant upregulation (2.7- to 5.7-fold; P ≤ 0.01) of growth factors and cytokines including IL1β, MMP3, IL6, and IL8. The paracrine effects of damaged quiescent cells consistently increased the proliferation and invasion of prostate cancer cells and promoted cell survival and resistance to apoptosis following exposure to chemotherapy.Implications: Benign quiescent cells in the TME respond to genotoxic stress by inducing a secretory program capable of promoting therapy resistance. Developing approaches to suppress the secretory program may improve treatment responses. Mol Cancer Res; 15(7); 842-51. ©2017 AACR.
| S-EPMC5859576 | biostudies-literature
Project description:This SuperSeries is composed of the following subset Series: GSE8542: BY4742 Quiescent and Non-quiescent replicates GSE8558: Proteinase K treatment of Q and NQ cells GSE8559: S288c Quiescent and Non-quiescent replicates GSE8560: Mutant1 GSE8561: Mutant2 Refer to individual Series
2010-05-29 | E-GEOD-8624 | biostudies-arrayexpress
Project description:Cancer develops in a complex environment that encompasses a wide spectrum of benign cell types, while the local microenvironment reduces the efficacy of multiple forms of cancer therapies. The DNA damage secretory program (DDSP) provoked by the side effects of genotoxic therapeutics results in cellular senescence and the senescence-associated secretory phenotype (SASP), the side effects of the latter frequently fueling advanced pathologies particularly therapeutic resistance. However, candidate approaches to prevent or circumvent the SASP development remains limited. We treated PSC27, a primary normal human prostate stromal cell line, with the genoxotic agents hereby represented by bleomycin, to investigate the relevant mechanisms. In order to control the SASP development, a group of potential SASP inhibitors were applied including p38MAPK, mTOR and TAK1 suppressors. The purpose was to compare the efficacy and effectiveness of these chemicals in combinatin with typical anticancer drugs in minimizing the secretory phenotype upon DNA damage that functionally remodels human stromal cells.
2018-12-27 | GSE90866 | GEO
Project description:The DNA damage secretory program (DDSP) provoked by the side effects of genotoxic therapeutics results in senescence associated secretory phenotype (SASP) and fuels advanced pathologies particularly cancer resistance. However, the complete mechanism underlying SASP development in the tumor microenvironment (TME) remains unclear. We treated PSC27, a primary normal human prostate stromal cell line, with two distinct groups of chemotherapeutic drugs that are either genotoxic or not, and determined the key molecules and their associated pathways responsible for development of a typical SASP phenotype under DNA damage conditions.
2018-08-31 | GSE82033 | GEO
Project description:Protein synthesis and autophagic degradation are regulated in an opposite manner by mammalian target of rapamycin (mTOR), whereas under certain conditions it would be beneficial if they occured in unison to handle rapid protein turnover. We observed a distinct cellular compartment at the trans-side of the Golgi apparatus, the ‘TOR-autophagy spatial coupling compartment’ (TASCC), where (auto)lysosomes and mTOR accumulated during Ras-induced senescence. mTOR recruitment to the TASCC was amino acid- and Rag guanosine triphosphatase (GTPase)-dependent, and disruption of mTOR localization to the TASCC suppressed interleukin-6/8 synthesis. TASCC-formation was observed during macrophage differentiation and in glomerular podocytes; both displayed increased protein secretion. The spatial coupling of cells’ catabolic and anabolic machinery could augment their respective functions and facilitate the mass synthesis of secretory proteins. To compare gene expression profile between growing and oncogenic Ras induced senescence, 4OHT inducible ER:H-RasV12 was stably expressed in IMR90 human diploid fibroblasts. Total RNA was isolated from day 0 and day 4 after 4OHT addition. There were 3 biological replicates for each of day0 and day 4 timepoints.
2011-05-04 | E-GEOD-28464 | biostudies-arrayexpress
Project description:Gene expression after mammosphere culture, quiescent single cells
| EGAD00010001964 | EGA
Project description:The epithelial lining of the small intestine is continuously renewed from a small number of stem cells including Lgr5 expressing crypt base cells that have been shown to be a rapidly cycling stem cell population in homeostasis. Alternative markers of intestinal stem cells have variously identified populations as rapidly cycling or quiescent with proposed roles for the latter as a parallel or reserve stem cell population. However, the exact nature of quiescent crypt cells remains unknown. Here by applying novel mouse models that permit their isolation and characterisation as label-retaining cells (LRCs), and for the first time performing lineage tracing from them, we show quiescent cells to be committed secretory precursors that are capable of recall to the stem cell state. We reveal LRCs to be a small subset of the rapidly cycling Lgr5 expressing population committed along the Paneth-enteroendocrine lineage. Significantly, after injury and subsequent regeneration they are clonogenic, as shown by both lineage tracing and organoid growth demonstrating that they can be recalled to the stem cell pool. These findings in establishing quiescent cells as an effective clonogenic reserve during injury provides a motivation for investigating their role in the maintenance of cancer growth following adjuvant treatment. Six age and sex (female) matched Cyp1a1-H2B-YFP mice ten days post βNF induction were used comparing three cell populations from each. Following epithelial isolation, single cell preparation and staining with anti-CD24 anitbody and UEA-1 lectin, 30,000 cells were flow sorted for each population: Paneth cells (Paneth) were defined as CD24+/UEA+, YFP-LRCs (YFPpos) as CD24+/UEA-/YFP+ and LCCs (YFPneg) as CD24+/UEA-/YFP-. Microarray expression comparison was then performed to identify unique markers of each population. RNA amplification and hybridisation was performed at the Paterson Institute, Manchester, UK, Microarray Facility using Nugen Ovation Pico WTA System for amplification and then hybridisation to a Mouse Exon 1.0 ST Array. Arrays were scanned using an Affymetrix GeneChip scanner 3000 running GCOS software.
2013-02-27 | E-GEOD-43772 | biostudies-arrayexpress
Project description:The epithelial lining of the small intestine is continuously renewed from a small number of stem cells including Lgr5 expressing crypt base cells that have been shown to be a rapidly cycling stem cell population in homeostasis. Alternative markers of intestinal stem cells have variously identified populations as rapidly cycling or quiescent with proposed roles for the latter as a parallel or reserve stem cell population. However, the exact nature of quiescent crypt cells remains unknown. Here by applying novel mouse models that permit their isolation and characterisation as label-retaining cells (LRCs), and for the first time performing lineage tracing from them, we show quiescent cells to be committed secretory precursors that are capable of recall to the stem cell state. We reveal LRCs to be a small subset of the rapidly cycling Lgr5 expressing population committed along the Paneth-enteroendocrine lineage. Significantly, after injury and subsequent regeneration they are clonogenic, as shown by both lineage tracing and organoid growth demonstrating that they can be recalled to the stem cell pool. These findings in establishing quiescent cells as an effective clonogenic reserve during injury provides a motivation for investigating their role in the maintenance of cancer growth following adjuvant treatment.
2013-02-27 | GSE43772 | GEO
Project description:The goal of the study was to characterize the whole genome transcriptome profiles of human ameloblasts and odontoblasts, evaluate molecular pathways and advance our knowledge of the human tooth development. We found that during primary tooth formation, odontoblasts expressed 14,802 genes, presecretory ameloblasts 15,179 genes and secretory ameloblasts 14,526 genes. Four human fetuses were obtained at ages 15-20 weeks gestation, immediately placed on ice and the tooth buds dissected from the jaws, placed in RNAlater and refrigerated at 4C for 1-4 weeks to allow decalcification by EDTA. The tissue was then frozen and stored at -80C. The tissue was sectioned at -35C at a thickness of 7 microns. These sections were used for laser capture microdissection (LCM) to isolate the human odontoblasts and ameloblasts in different stages of enamel formation, using static image settings. In total, 4 odontoblast, 4 pre-secretory ameloblast and 4 secretory ameloblast pooled samples were used for RNA extraction and microarray analysis.
2014-11-14 | E-GEOD-63289 | biostudies-arrayexpress
Project description:Quiescent stem cells of glioblastoma (GBM), a malignant primary brain tumor, are potential sources for recurrence after therapy. However, the gene expression program underlying the physiology of GBM stem cells remains unclear. We have isolated quiescent GBM cells by engineering them with a knock-in H2B-GFP proliferation reporter and expanding them in a 3D tumor organoid model that mimics tumor heterogeneity. H2B-GFP label retaining quiescent cells were subjected to stem cell assays and RNA-Seq gene expression analysis. While quiescent GBM cells were similar in clonal culture assays to their proliferative counterparts, they displayed higher therapy resistance. Interestingly, quiescent GBM cells upregulated epithelial-mesenchymal transition (EMT) genes and genes of extracellular matrix components. Our findings connect quiescent GBM cells with an EMT-like shift, possibly explaining how GBM stem cells achieve high therapy resistance and invasiveness, and suggest new targets to abrogate GBM.
2019-04-22 | GSE114574 | GEO