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Gene expression profiling of mouse breast tumor tissue after injection of 4T1 therapy-induced senesence derived sEVs

ABSTRACT: TNBC, associated with poor prognosis and high tumour recurrence, are often treated with anti-mitotic drugs. However, cells may bypass treatment-induced cell death via mitotic slippage, resulting in multinucleated polyploid cells and senescence activation. Senescent cancer cells represent a population of residual disease and are highly secretory. The SASP elicited is enriched in soluble cytokines linked to tumor recurrence and distant metastasis. In contrast, sEVs derived from senescent cancer cells represent an underappreciated aspect of SASP and its mechanistic role in mediating paracrine effects remains poorly-understood. Here, we show senescent sEVs as a distinct population of SASP that could elicit anti-tumor activity.

ORGANISM(S): Mus musculus

PROVIDER: GSE237710 | GEO | 2024/03/25

REPOSITORIES: GEO

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Gene expression profiling of MDA-MB-231 cells incubated with therapy induced senescence derived small extracellular vesicles

Project description:TNBC, associated with poor prognosis and high tumour recurrence, are often treated with anti-mitotic drugs. However, cells may bypass treatment-induced cell death via mitotic slippage, resulting in multinucleated polyploid cells and senescence activation. Senescent cancer cells represent a population of residual disease and are highly secretory. The SASP elicited is enriched in soluble cytokines linked to tumor recurrence and distant metastasis. In contrast, sEVs derived from senescent cancer cells represent an underappreciated aspect of SASP and its mechanistic role in mediating paracrine effects remains poorly-understood. Here, we show senescent sEVs as a distinct population of SASP that could elicit anti-tumor activity.

2024-03-25 | GSE238165 | GEO

Gene expression profiling of MDA-MB-231 cells incubated with therapy induced senescence secretome

2024-03-25 | GSE236953 | GEO

Mitotic stress is an integral part of the oncogene-induced senescence program that promotes multinucleation and cell cycle arrest

Project description:Oncogene-induced senescence (OIS) is a tumor suppression mechanism that blocks cell proliferation in response to oncogenic signalling. OIS is frequently accompanied by multinucleation; however, the origin of this is unknown. Here we show that multinucleate OIS cells originated mostly from failed mitosis. Prior to senescence, mutant RasV12 activation in primary human fibroblasts compromised mitosis, associated with abnormal expression of mitotic genes that enter M-phase. Simultaneously, RasV12 activation enhanced survival of damaged mitoses, culminating in extended mitotic arrest and aberrant exit from mitosis via mitotic slippage. ERK-dependent transcriptional up-regulation of Mcl1 was responsible for enhanced slippage of cells with mitotic defects and subsequent cell survival. Importantly, mitotic slippage and oncogene signalling synergistically induced senescence and key senescence regulators p21 and p16. We propose that activated Ras induces transcriptional changes that predispose cells undergoing OIS to mitotic stress and multinucleation. We used RNA-seq of IMR90 cells with inducible expression of oncogenic RasV12 that were synchronised in mitosis, to characterise the nature of mitotic defects that lead to multinucleation of oncogene-induced senescent cells

2015-08-13 | E-GEOD-70668 | biostudies-arrayexpress

Mitotic stress is an integral part of the oncogene-induced senescence program that promotes multinucleation and cell cycle arrest

2015-08-13 | GSE70668 | GEO

Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer

Project description:Accumulation of senescent cells in the tumour microenvironment can drive tumourigenesis in a paracrine manner through the senescence-associated secretory phenotype (SASP). Using a new p16-FDR mouse line, we show that macrophages and endothelial cells are the predominant senescent cell types in murine KRAS-driven lung tumours. Single cell transcriptomics identify a population of tumour-associated macrophages, expressing a unique array of pro-tumourigenic SASP factors and surface proteins, that are also present in normal aged lungs. Genetic or senolytic ablation of senescent cells, and macrophage depletion, result in a significant reduction in tumour burden and increased mouse survival of KRAS-driven lung cancer models. Of translational relevance, we reveal the presence of macrophages with senescent features in human lung premalignant lesions, but not in adenocarcinomas. Together, our results have uncovered a population of senescent macrophages contributing to the initiation and progression of lung cancer, thus opening potential therapeutic avenues and cancer preventative strategies.

2023-06-02 | GSE230054 | GEO

Post-slippage cells increase expression of factors associated with SASP.

Project description:Post-slippage cells increase expression of factors associated with SASP.

| PRJNA471655 | ENA

Oxylipin biosynthesis reinforces cellular senescence through a RAS/p53 feedback loop and allows detection of senolysis

Project description:Cellular senescence is a stress or damage response that causes a permanent proliferative arrest and secretion of numerous factors with potent biological activities. This senescence-associated secretory phenotype (SASP) has been characterized largely for secreted proteins that participate in embryogenesis, wound healing, inflammation and many age-related pathologies. By contrast, lipid components of the SASP are understudied. We show that senescent cells activate the biosynthesis of several oxylipins that promote segments of the SASP and reinforce the proliferative arrest. Notably, senescent cells synthesize and accumulate an unstudied intracellular prostaglandin, 1a,1b-dihomo-15-deoxy-delta-12,14-prostaglandin J2. Released 15-deoxy-delta-12,14-prostaglandin J2 is a biomarker of senolysis in culture and in vivo. This and other prostaglandin D2-related lipids promote the senescence arrest and SASP by activating RAS signaling. These data identify an important aspect of cellular senescence and a method to detect senolysis

2021-02-20 | ST001708 | MetabolomicsWorkbench

RNA seq of prostate gland from WT, PTEN pc -/- and PTEN pc-/-;P53 -/- mice

Project description:Acute Pten loss initiates prostate tumorigenesis characterized by cellular senescence response. Senescent cells secrete a variety of pro inflammatory factors in the tumor microenvironment, which can support the survival, outgrowth and migration of tumor cells. Here we examine cytokines and cytokines-related factors gene expression in Ptenpc-/- senescent and in Ptenpc-/-; Trp53pc-/- non senescent tumors. RNAseq analysis confirmed the presence of cytokines, which were specifically up- and down-regulated in Ptenpc-/- senescent tumors (“core-SASP”) we also found a number of upregulated secreted factors that were “senescence-unrelated” both present in both Ptenpc-/- and Ptenpc-/-; Trp53pc-/- tumors.

2020-10-09 | E-MTAB-9624 | biostudies-arrayexpress

A BDNF-TrkB autocrine loop enhances senescent cell viability [RNA-seq]

Project description:Cellular senescence is characterized by cell cycle arrest, resistance to apoptosis, and a senescence-associated secretory phenotype (SASP) whereby cells secrete pro-inflammatory and tissue-remodeling factors. Given that the SASP exacerbates age-associated pathologies, some aging interventions selectively eliminate senescent cells. In this study, a drug library screen uncovered TrkB (NTRK2) inhibitors as selectively capable of triggering apoptosis of senescent, but not proliferating, human fibroblasts. Senescent cells expressed high levels of TrkB, which supported senescent cell viability, and secreted the TrkB ligand BDNF. The reduced viability of senescent cells after ablating BDNF function supported an autocrine function for TrkB and BDNF, and the increased expression of BCL2L2 through ERK5, downstream of BDNF-TrkB, favored senescent cell survival. Strikingly, treatment with TrkB inhibitors reduced the accumulation of senescent cells in aged mouse organs. Our results suggest that the SASP factor BDNF promotes cell survival by activating TrkB and is a promising therapeutic target to reduce the senescent cell burden.

2022-09-20 | GSE190998 | GEO

Whole-Body Senescent Cell Clearance Alleviates Age-Related Brain Inflammation and Cognitive Impairment in Mice

Project description:Cellular senescence is characterized by an irreversible cell cycle arrest and a pro-inflammatory senescence-associated secretory phenotype (SASP), which is a major contributor to aging and age-related diseases. Clearance of senescent cells has been shown to improve brain function in mouse models of neurodegenerative diseases. However, it is still unknown whether senescent cell clearance alleviates cognitive dysfunction during the aging process. To investigate this, we first conducted single-nuclei and single-cell RNA-seq in the hippocampus from young and aged mice. We observed an age-dependent increase in p16Ink4a senescent cells, which was more pronounced in microglia and oligodendrocyte progenitor cells and characterized by a SASP. We then aged INK-ATTAC mice, in which p16Ink4a-positive senescent cells can be genetically eliminated upon treatment with the drug AP20187 and treated them either with AP20187 or with the senolytic cocktail Dasatinib and Quercetin. We observed that both strategies resulted in a decrease in p16Ink4a exclusively in the microglial population, resulting in reduced microglial activation and reduced expression of SASP factors. Importantly, both approaches significantly improved cognitive function in aged mice. Our data provide proof-of-concept for senolytic interventions’ being a potential therapeutic avenue for alleviating age-associated cognitive impairment.

2021-02-06 | GSE161340 | GEO

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