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Myeloma-modified adipocytes exhibit a senescent-associated secretory phenotype

ABSTRACT: Myeloma-modified adipocytes exhibit a senescent-associated secretory phenotype

PROVIDER: PRJNA589536 | ENA |

REPOSITORIES: ENA

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Myeloma-modified adipocytes exhibit a senescent-associated secretory phenotype

Project description:Bone marrow -adipocytes (BMAs) have recently been implicated in accelerating bone metastatic cancers such as AML and breast cancer. Importantly, bone marrow adipose tissue (BMAT) expands with aging and obesity- two key risk factors in multiple myeloma (MM) disease prevalence- suggesting that BMAs influence and are influenced by myeloma cells in the marrow. Here we examined how myeloma cells affect adipocytes and provide evidence that MM cells alter adipocyte gene expression and cytokine secretion profiles, creating a “MM-associated” adipocyte (MM-adipocyte) phenotype. Our findings indicate that: (1) Multiple myeloma cells decrease BM adiposity in vitro, in myeloma animal models, and in clinical samples, (2) myeloma induces widespread gene expression and phenotypic changes in adipocytes in vitro, most notable, the induction of a senescent-like phenotype in BMAs, (3) MM-adipocytes affect myeloma cell cycle, drug sensitivity, and aggressiveness, illuminating a new driver of MM cell evolution in a drug resistant clone. We demonstrate that myeloma cells exposed to MM-adipocytes are rescued from dexamethasone-induced cell cycle arrest and have increased expression of FKBP5, a potential drug resistance gene. Our findings in patients confirm that BMAs are dynamic during myeloma disease progression (decrease during MM initiation, recover during disease remission) and that the interactions between BMAs and MM cells have previously unappreciated implications in the understanding and treatment of myeloma.

2021-03-10 | GSE140374 | GEO

Myeloma-modified 3T3-L1 adipocytes exhibit aberrant gene expression profiles

Project description:Myeloma-modified 3T3-L1 adipocytes exhibit aberrant gene expression profiles

| PRJNA599429 | ENA

Myeloma-modified 3T3-L1 adipocytes exhibit aberrant gene expression profiles [experiment 2]

Project description:Myeloma-modified 3T3-L1 adipocytes exhibit aberrant gene expression profiles [experiment 2]

| PRJNA599433 | ENA

Myeloma-modified 3T3-L1 adipocytes exhibit aberrant gene expression profiles [experiment 1]

Project description:Myeloma-modified 3T3-L1 adipocytes exhibit aberrant gene expression profiles [experiment 1]

| PRJNA599434 | ENA

Senescent beta-cells exhibit a unique secretory phenotype that promotes inflammation and remodeling of the extracellular environment

Project description:Senescent beta-cells exhibit a unique secretory phenotype that promotes inflammation and remodeling of the extracellular environment

| PRJNA630731 | ENA

Myeloma-Modified Adipocytes Exhibit Metabolic Dysfunction and a Senescence-Associated Secretory Phenotype.

Project description: Not available

| S-EPMC7854508 | biostudies-literature

Senescent beta-cells exhibit a unique secretory phenotype that promotes inflammation and remodeling of the extracellular environment

Project description:Type 2 Diabetes (T2D) patients have higher proportions of senescent beta-cells than their non-diabetic counterparts (Aguayo-Mazzucato et al., 2019). Senescent beta-cells may propagate dysfunction in neighboring cells through the paracrine effects of the senescence-associated secretory phenotype (SASP). To address the heterogeneity in beta-cell SASP expression and its role in T2D, we measured expression levels of beta-cell SASP signature genes in a mouse model of acute insulin resistance using the insulin receptor antagonist, S961. We have previously shown that this model induces hyperglycemia and accelerates beta-cell senescence (Aguayo-Mazzucato et al., 2019). Pancreatic islets were isolated from 3 groups of mice: a control group, a treated group of mice with surgically installed osmotic pumps secreting S961 for 2 weeks, and a third group in which mice recovered from S961 treatment for two weeks. During treatment, mice developed marked hyperglycemia and hyperinsulinemia which was completely reversed during the two-week recovery period. Islets were dispersed into single cells and scRNASeq was performed using the 10x Genomics Chromium Single Cell Gene Expression Assay.

2021-04-06 | GSE149984 | GEO

Genome-wide expression analysis of young, senescent and p38MAPK-inhibitited senescent human fibroblasts.

Project description:We utilized whole genome sequencing of mRNA (RNA-seq) to understand the extent to which the senescence-associated secretory phenotype is regulated by p38MAPK Examination of replicates of young, senescent or p38MAPK-inhibited senescent BJ human foreskin fibroblasts.

2014-04-01 | E-GEOD-56293 | biostudies-arrayexpress

Glucocorticoid-stimulated senescence phenotype in differentiated bone marrow adipocytes treated with PPARgamma inhibitor

Project description:Glucocorticoids, powerful anti-inflammatory and immunosuppressive agents, can decrease bone mass and quality and increase bone marrow adiposity. Here, we show that a small number of bone marrow adipocytes (BMAds) in mice undergo rapid cellular senescence in response to glucocorticoid treatment. The senescent BMAds acquire a senescence-associated secretory phenotype (SASP), which reinforces and spreads senescence in the bone/bone marrow microenvironment in a paracrine manner. Mechanistically, glucocorticoid treatment increases the synthesis of oxylipins such as 15d-PGJ2 in BMAds to positively regulate the activity of PPARγ, which stimulates the expression of key cellular senescence effector genes. PPARγ activation, in turn, promotes oxylipin synthesis in BMAds, forming a positive feedback loop. Inhibition of the initial BMAd senescence by deleting p16INK4a from adipocytes or pharmacological suppression of the SASP efficiently interrupts the secondary spread of senescent cells and alleviates glucocorticoid-induced bone deficits. We identify senescent BMAds as initial mediators for glucocorticoid-induced bone deterioration and reveal a lipid metabolism circuit that robustly triggers the senescence of BMAds.

2023-06-09 | GSE205732 | GEO

Obesity and hyperinsulinemia drive adipocytes to activate a cell cycle program and senesce

Project description:Obesity is considered an important factor for many chronic diseases, including diabetes, cardiovascular disease and cancer. The expansion of adipose tissue in obesity is due to an increase in both adipocyte progenitor differentiation and mature adipocyte cell size. Adipocytes, however, are thought to be unable to divide or enter cell cycle. We demonstrate that mature human adipocytes unexpectedly display a gene and protein signature of cell cycle re-entry. Adipocyte cell cycle progression associates with obesity and hyperinsulinemia, with a concomitant increase in cell size, nuclear size and nuclear DNA content. However, chronic hyperinsulinemia in vitro or in patients, is associated with subsequent cell cycle exit, leading to a premature senescent transcriptomic and secretory profile in adipocytes. Premature senescence is rapidly becoming recognized as an important mediator of stress-induced tissue dysfunction. By demonstrating that adipocytes can re-enter cell cycle we define a mechanism for how mature, human adipocytes senesce and demonstrate that by targeting the adipocyte cell cycle program it is possible to impact adipocyte senescence and obesity-associated adipose tissue inflammation.

| EGAS00001005770 | EGA

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