IDENTIFICATION OF A NOVEL GENETIC PROGRAM AT THE INITIATION OF COLON CANCER DEVELOPMENT.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE70170 | GEO | 2018/06/30
REPOSITORIES: GEO
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Project description:Molecular distinctions between the stasis and telomere attrition senescence barriers in cultured human mammary epithelial cells Normal human epithelial cells in culture have generally shown a limited proliferative potential of ~10-40 population doublings before encountering a stress-associated senescence barrier (stasis) associated with elevated levels of cyclin-dependent kinase inhibitors p16 and/or p21. We now show that simple changes in media composition can expand the proliferative potential of human mammary epithelial cells (HMEC) initiated as primary cultures to 50-60 population doublings, followed by p16(+), senescence-associated b-galactosidase(+) stasis. We compared the properties of growing and senescent pre-stasis HMEC with growing and senescent post-selection HMEC, i.e., cells grown in a serum-free medium that overcame stasis via silencing of p16 expression and that display senescence associated with telomere dysfunction. Cultured pre-stasis populations contained cells expressing markers associated with luminal and myoepithelial HMEC lineages in vivo, in contrast to the basal-like phenotype of the post-selection HMEC. Gene transcript and protein expression, DNA damage-associated markers, mean TRF length, and genomic stability, differed significantly between HMEC populations at the stasis vs. telomere attrition senescence barriers. Senescent isogenic fibroblasts showed greater similarity to HMEC at stasis than at telomere attrition, although their gene transcript profile was distinct from HMEC at both senescence barriers. These studies support our model of the senescence barriers encountered by cultured HMEC in which the first barrier, stasis, is Rb-mediated and independent of telomere length, while a second barrier (agonescence or crisis) results from telomere attrition leading to telomere dysfunction. Additionally, the ability to maintain long-term growth of genomically stable multi-lineage pre-stasis HMEC populations can greatly enhance experimentation with normal HMEC. 48 samples from Human Mammary Epithelial cells which includes samples from four different individuals at different passage levels which includes prestasis,intermediate,post selection and agonesence stages of cell cycle.
2010-05-28 | E-GEOD-16058 | biostudies-arrayexpress
Project description:Telomere shortening in populations of human mammary epithelial cells (HMECs) that survive early replicative arrest (M0) by the inactivation of p16INK4A during cell culture on plastic dishes leads to a state of permanent replicative arrest termed senescence. While culture of HMECs on feeder layers abrogates M0 and p16INK4A inactivation, progressive telomere attrition in these cells also eventually results in permanent replicative arrest. Expression of telomerase prevents both senescence on plastic (S-P) and senescence on feeder layers (S-FL) in HMECs, as it does also in cultured primary human fibroblasts. We report here that the gene expression profiles of senescence in HMECs of the same lineage maintained under different culture conditions showed surprisingly little commonality. Moreover, neither of these senescence-associated profiles in HMECs resembles the profile for senescence in human fibroblasts. These results indicate that senescence-associated alterations in gene expression resulting from telomere attrition are affected by culture conditions as well as by cell origins, and argue that replicative senescence at the molecular level is a diverse rather than unique cellular process.
2005-11-01 | E-SMDB-2210 | biostudies-arrayexpress
Project description:Telomere shortening in populations of human mammary epithelial cells (HMECs) that survive early replicative arrest (M0) by the inactivation of p16INK4A during cell culture on plastic dishes leads to a state of permanent replicative arrest termed senescence. While culture of HMECs on feeder layers abrogates M0 and p16INK4A inactivation, progressive telomere attrition in these cells also eventually results in permanent replicative arrest. Expression of telomerase prevents both senescence on plastic (S-P) and senescence on feeder layers (S-FL) in HMECs, as it does also in cultured primary human fibroblasts. We report here that the gene expression profiles of senescence in HMECs of the same lineage maintained under different culture conditions showed surprisingly little commonality. Moreover, neither of these senescence-associated profiles in HMECs resembles the profile for senescence in human fibroblasts. These results indicate that senescence-associated alterations in gene expression resulting from telomere attrition are affected by culture conditions as well as by cell origins, and argue that replicative senescence at the molecular level is a diverse rather than unique cellular process.
2005-11-01 | E-SMDB-2046 | biostudies-arrayexpress
Project description:The aim of this study was to set up an in vitro model to highlight yet-unidentified mechanisms facilitating the escape of human colonic epithelial cells from chronic inflammation-induced senescence, and to define whether these mechanisms afford cells a resistance to oxidative stress thereby contributing to tumor initiation. By driving a specific genetic program (termed ALEP), as observed in ulcerative colitis and Crohn’s disease patients, transient expression of ZEB transcription factors buffers ROS deleterious effects and maintains intestinal stem cell (ISC) integrity. Nonetheless, as a perverse effect, maintenance of this program is likely to facilitate their neoplastic transformation and contribute to tumor initiation. We identified the quinolinate phosphoribosyltransferase enzyme (QPRT) as the main component of the ALEP-associated survival advantage. Here is mRNA expression data of second cohort of 50 sporadic primary colorectal carcinomas (CRC) resected from untreated patients used in conjunction with their QPRT values assessed by IHC. These 50 CRCs were scored for ALEP, Stem-like, Lgr5 and EphB2high signatures to test correlation with QPRT.
2021-05-06 | E-MTAB-4090 | biostudies-arrayexpress
Project description:Molecular distinctions between the stasis and telomere attrition senescence barriers in cultured human mammary epithelial cells Normal human epithelial cells in culture have generally shown a limited proliferative potential of ~10-40 population doublings before encountering a stress-associated senescence barrier (stasis) associated with elevated levels of cyclin-dependent kinase inhibitors p16 and/or p21. We now show that simple changes in media composition can expand the proliferative potential of human mammary epithelial cells (HMEC) initiated as primary cultures to 50-60 population doublings, followed by p16(+), senescence-associated b-galactosidase(+) stasis. We compared the properties of growing and senescent pre-stasis HMEC with growing and senescent post-selection HMEC, i.e., cells grown in a serum-free medium that overcame stasis via silencing of p16 expression and that display senescence associated with telomere dysfunction. Cultured pre-stasis populations contained cells expressing markers associated with luminal and myoepithelial HMEC lineages in vivo, in contrast to the basal-like phenotype of the post-selection HMEC. Gene transcript and protein expression, DNA damage-associated markers, mean TRF length, and genomic stability, differed significantly between HMEC populations at the stasis vs. telomere attrition senescence barriers. Senescent isogenic fibroblasts showed greater similarity to HMEC at stasis than at telomere attrition, although their gene transcript profile was distinct from HMEC at both senescence barriers. These studies support our model of the senescence barriers encountered by cultured HMEC in which the first barrier, stasis, is Rb-mediated and independent of telomere length, while a second barrier (agonescence or crisis) results from telomere attrition leading to telomere dysfunction. Additionally, the ability to maintain long-term growth of genomically stable multi-lineage pre-stasis HMEC populations can greatly enhance experimentation with normal HMEC.
2010-05-12 | GSE16058 | GEO
Project description:Aging organisms accumulate senescent cells, which are the result of exposure to important stress such as telomere attrition, irradiation, oncogene activation, oxidative stress or cytotoxic drugs. These senescent cells are characterized by a stable cell cycle arrest and an important secretion of pro-inflammatory factors. This senescence-associated secretory phenotype (SASP) has been shown to promote chronic inflammation leading to age-associated diseases. While a lot of in vitro models of senescence focus on senescent fibroblasts, it has been shown that a major portion of the burden of senescent cells in old mice are macrophages. Senescent macrophages have been shown to contribute to atherosclerosis, neurodegenerative diseases and macular degeneration. Yet little is known about senescent macrophages. Considering their potential role in age-associated diseases, we think these senescent macrophages and their secretions need to be investigated. Here we aimed to establish and characterize an in vitro model for oncogene-induced senescence in macrophages, to characterize secretions of these senescent macrophages and to assess impacts of these secretions on recipient cells.
2021-06-29 | GSE153508 | GEO
Project description:Telomere erosion contributes to age-associated tissue dysfunction and senescence, and p53 plays a crucial role in this response. We undertook a genome-wide screen to identify gene deletions that sensitized p53-positive human cells to loss of telomere integrity, and uncovered a previously unannotated gene, C16ORF72, which we term Telomere Attrition and p53 Response 1: TAPR1. CRISPR-Cas9 mediated deletion of TAPR1 led to elevated p53 and induction of p53 transcriptional targets. TAPR1-disrupted cells exhibited a synthetic-sick relationship with the loss of telomerase, or treatment with the topoisomerase II inhibitor doxorubicin. Stabilization of p53 with nutlin-3a further decreased cell fitness in cells lacking TAPR1 or telomerase, whereas deletion of TP53 rescued the decreased fitness of TAPR1-deleted cells. We propose that TAPR1 regulates p53 turnover, thereby tapering the p53-dependent response to telomere erosion. We discuss the possible implications of such a mechanism in the preservation of genome integrity during senescence or aging.
2021-03-04 | PXD022128 | Pride
Project description:The molecular mechanisms that drive hematopoietic stem cell (HSC) functional decline under conditions of stress are not completely understood. Here, in light of the recent advances in single-cell technologies, we sought to redefine the transcriptional and epigenetic landscape of mouse and human hematopoietic stem cells (HSCs) under telomeric stress, as that induced by pathogenic germline mutations in telomerase complex genes. These analyses revealed that telomere attrition maintains HSCs in a state of persistent metabolic activation and differentiation towards the megakaryocytic lineage through the cell-intrinsic upregulation of interferon (IFN) signaling response, which directly comprises HSCs’ self-renewal capabilities and eventually leads to their exhaustion. Telomerase reactivation completely restored HSC transcriptional homeostasis at the single-cell level, overcame enhanced megakaryocytic differentiation and significantly ameliorated HSCs’ repopulation capacity in the setting of competitive transplantation, suggesting that HSCs can repristinate their function upon telomere damage resolution. This study challenges the long-standing hypothesis that telomere attrition limits the proliferative potential of HSCs by inducing apoptosis or senescence and suggests that early intervention targeting the IFN axis could prevent bone marrow failure syndromes in patients with pathogenic mutations affecting telomere maintenance.
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Project description:The molecular mechanisms that drive hematopoietic stem cell (HSC) functional decline under conditions of stress are not completely understood. Here, in light of the recent advances in single-cell technologies, we sought to redefine the transcriptional and epigenetic landscape of mouse and human hematopoietic stem cells (HSCs) under telomeric stress, as that induced by pathogenic germline mutations in telomerase complex genes. These analyses revealed that telomere attrition maintains HSCs in a state of persistent metabolic activation and differentiation towards the megakaryocytic lineage through the cell-intrinsic upregulation of interferon (IFN) signaling response, which directly comprises HSCs’ self-renewal capabilities and eventually leads to their exhaustion. Telomerase reactivation completely restored HSC transcriptional homeostasis at the single-cell level, overcame enhanced megakaryocytic differentiation and significantly ameliorated HSCs’ repopulation capacity in the setting of competitive transplantation, suggesting that HSCs can repristinate their function upon telomere damage resolution. This study challenges the long-standing hypothesis that telomere attrition limits the proliferative potential of HSCs by inducing apoptosis or senescence and suggests that early intervention targeting the IFN axis could prevent bone marrow failure syndromes in patients with pathogenic mutations affecting telomere maintenance.
2021-10-23 | GSE169709 | GEO
Project description:Cellular senescence is a program of irreversible cell cycle arrest that normal cells undergo in response to progressive shortening of telomeres, changes in telomeric structure, oncogene activation or oxidative stress. The underlying signalling pathways, potentially of major clinicopathological relevance, are unknown. A major stumbling block to studying senescence has been the absence of suitable model systems because of the asynchrony of this process in heterogeneous cell populations. To simplify this process many investigators study oncogene-induced senescence due to expression of activated oncogenes where senescence occurs prematurely without telomere attrition and can be induced acutely in a variety of cell types. We have taken a different approach by making use of the finding that reconstitution of telomerase activity by introduction of the catalytic subunit of human telomerase alone is incapable of immortalising all human somatic cells, but inactivation of the p16-pRB and p53-p21 pathways are required in addition. The ability of SV40 large T antigen to inactivate the p16-pRB and p53-p21 pathways has enabled us to use a thermolabile mutant of LT antigen, in conjunction with hTERT, to develop conditionally immortalised human (HMF3A) fibroblasts that are immortal but undergo an irreversible growth arrest when the thermolabile LT antigen is inactivated leading to activation of pRB and p53. When these cells cease dividing, senescence-associated- b-galactosidase activity is induced and the growth-arrested cells have morphological features and express genes in common with senescent cells. Since these cells growth arrest in a synchronous manner they are an excellent starting point for dissecting the pathways that underlie cellular senescence and act downstream of p16-pRB and p53-p21 pathways. We have combined genome-wide expression profiling with genetic complementation to undertake identification of genes that are differentially expressed when these conditionally immortalised human fibroblasts undergo senescence upon activation of the p16-pRB and p53-p21 tumour suppressor pathways. Genes differentially expressed upon senescence will be identified by comparing arrays from growing versus senescent cells. Changes in gene expression due to the temperature shift will be eliminated by comparing with array data from the non-conditional HMF3S cells grown at 34°C ±0.5°C and 38°C ±0.5°C. To determine if the changes in gene expression upon senescence are specific and reversible, the set of differential genes will then be overlaid with array data from cells in which senescence has been bypassed by inactivation of the p16-pRB and p53-p21 tumour suppressor pathways
2011-01-21 | E-GEOD-24810 | biostudies-arrayexpress