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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 1]

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

| PRJNA599434 | 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

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:Bone marrow adipocytes (BMAd) have recently been implicated in accelerating bone metastatic cancers, such as acute myelogenous leukemia and breast cancer. Importantly, bone marrow adipose tissue (BMAT) expands with aging and obesity, two key risk factors in multiple myeloma disease prevalence, suggesting that BMAds may influence and be influenced by myeloma cells in the marrow. Here, we provide evidence that reciprocal interactions and cross-regulation of myeloma cells and BMAds play a role in multiple myeloma pathogenesis and treatment response. Bone marrow biopsies from patients with multiple myeloma revealed significant loss of BMAT with myeloma cell infiltration of the marrow, whereas BMAT was restored after treatment for multiple myeloma. Myeloma cells reduced BMAT in different preclinical murine models of multiple myeloma and in vitro using myeloma cell-adipocyte cocultures. In addition, multiple myeloma cells altered adipocyte gene expression and cytokine secretory profiles, which were also associated with bioenergetic changes and induction of a senescent-like phenotype. In vivo, senescence markers were also increased in the bone marrow of tumor-burdened mice. BMAds, in turn, provided resistance to dexamethasone-induced cell-cycle arrest and apoptosis, illuminating a new possible driver of myeloma cell evolution in a drug-resistant clone. Our findings reveal that bidirectional interactions between BMAds and myeloma cells have significant implications for the pathogenesis and treatment of multiple myeloma. Targeting senescence in the BMAd or other bone marrow cells may represent a novel therapeutic approach for treatment of multiple myeloma. SIGNIFICANCE: This study changes the foundational understanding of how cancer cells hijack the bone marrow microenvironment and demonstrates that tumor cells induce senescence and metabolic changes in adipocytes, potentially driving new therapeutic directions.

| 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

Senescent microglia limit remyelination through the senescence associated secretory phenotype

Project description:Senescent microglia limit remyelination through the senescence associated secretory phenotype

| PRJNA1117003 | ENA

Senescent microglia limit remyelination through the senescence associated secretory phenotype

Project description:The capacity to regenerate myelin in the central nervous system (CNS) diminishes with age. This decline is particularly evident in multiple sclerosis (MS), which has been suggested to exhibit features of accelerated biological aging. Whether cellular senescence, a hallmark of aging, contributes to remyelination impairment remains unknown. Here, we show that senescent cells (SCs) accumulate within demyelinated lesions after injury, and their elimination enhances remyelination in young mice but not in aged mice. In young mice, we observed the upregulation of senescence-associated transcripts primarily in microglia after demyelination, followed by their reduction during remyelination. However, in aged mice, senescence-associated factors persisted within lesions, correlating with inefficient remyelination. We found that SC elimination enhanced remyelination in young mice but was ineffective in aged mice. Proteomic analysis of senescence associated secretory phenotype (SASP) revealed elevated levels of CCL11/Eotaxin-1 in lesions, which was found to inhibit efficient oligodendrocyte maturation. These results suggest therapeutic targeting of SASP components, such as CCL11, may improve remyelination in aging and MS.

2025-02-03 | GSE268386 | GEO

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