Creatine mediated crosstalk between adipocytes and cancer cells regulates obesity-driven breast cancer
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE165273 | GEO | 2021/01/22
REPOSITORIES: GEO
Similar Datasets
Project description:Creatine mediated crosstalk between adipocytes and cancer cells regulates obesity-driven breast cancer
| PRJNA693853 | ENA
Project description:The mechanisms promoting disturbed white adipocyte function in obesity remain largely unclear. Herein, we integrate white adipose tissue (WAT) metabolomic and transcriptomic data from clinical cohorts and find that the WAT phosphocreatine/creatine ratio is increased and creatine kinase-B expression and activity is decreased in the obese state. . In human in vitro and murine in vivo models, we demonstrate that decreased phosphocreatine metabolism in white adipocytes alters AMPK activity via effects on ATP/ADP levels, independently of WAT beigeing. This disturbance promotes a pro-inflammatory profile characterized, in part, by increased CCL2 production. These data suggest that the phosphocreatine/creatine system links cellular energy shuttling with pro-inflammatory responses in human and murine white adipocytes. Our findings provide unexpected perspectives on the mechanisms driving WAT inflammation in obesity and may present avenues to target adipocyte dysfunction.
2022-01-27 | GSE192361 | GEO
Project description:Obesity is a risk factor for postmenopausal ERα (+) breast cancer. The metabolites from serum that contribute to this risk and how these factors affect ERα signaling are not known. Using whole metabolite profiling and a detection panel for proteins, we identified biomarkers that were differentially present in serum from obese vs. non-obese postmenopausal women, and we validated these factors in two separate cohorts of postmenopausal women who either developed breast cancer or those who were obese and lost weight after the onset of menopause. In vitro assays identified free fatty acids (FFAs), in particular oleic acid (OA) as serum factors that correlate with increased proliferation and aggressiveness in ERα(+) breast cancer cells by. FFAs activated both ERα and mTOR pathways and rewired metabolism in breast cancer cells. Pathway preferential estrogen-1 (PaPE-1), which target ERα and mTOR signaling, was able to block changes induced by FFAs. In fact, PaPEs were more effective in the presence of FFAs, suggesting a role for obesity-associated gene and metabolic rewiring in providing new targetable vulnerabilities for ERα-(+) breast cancer in postmenopausal women. Our findings provide a basis for preventing or inhibiting obesity-associated breast cancer by using PaPEs that would reverse these newly appreciated metabolic vulnerabilities of breast tumors in obese postmenopausal women.
2020-01-11 | GSE93510 | GEO
Project description:Obesity is a risk factor for postmenopausal ERα (+) breast cancer. The metabolites from serum that contribute to this risk and how these factors affect ERα signaling are not known. Using whole metabolite profiling and a detection panel for proteins, we identified biomarkers that were differentially present in serum from obese vs. non-obese postmenopausal women, and we validated these factors in two separate cohorts of postmenopausal women who either developed breast cancer or those who were obese and lost weight after the onset of menopause. In vitro assays identified free fatty acids (FFAs), in particular oleic acid (OA) as serum factors that correlate with increased proliferation and aggressiveness in ERα(+) breast cancer cells by. FFAs activated both ERα and mTOR pathways and rewired metabolism in breast cancer cells. Pathway preferential estrogen-1 (PaPE-1), which target ERα and mTOR signaling, was able to block changes induced by FFAs. In fact, PaPEs were more effective in the presence of FFAs, suggesting a role for obesity-associated gene and metabolic rewiring in providing new targetable vulnerabilities for ERα-(+) breast cancer in postmenopausal women. Our findings provide a basis for preventing or inhibiting obesity-associated breast cancer by using PaPEs that would reverse these newly appreciated metabolic vulnerabilities of breast tumors in obese postmenopausal women.
2020-01-11 | GSE93505 | GEO
Project description:The metabolic dependencies of cancer cells have significant potential to be exploited to improve the diagnosis and treatment of cancer. Creatine riboside (CR) is a novel urinary metabolite associated with risk and prognosis in lung and liver cancer. However, the source of high creatine riboside levels in cancer patients, as well as its implications for the treatment of these aggressive cancers remain unclear. By integrating RNA sequencing and whole exome sequencing of non-small cell lung cancer tissues we sought to understand the source of creatine riboside and the tumor biology associated with this novel metabolite. Utilising multiple lung and liver cancer cohorts, next generation sequencing data was combined with global metabolomics analysis of human tumors, and matched liquid biopsies together with functional studies to reveal that dysregulation of the mitochondrial urea cycle and nucleotide imbalance are associated with high creatine riboside levels and are indicators of poor prognosis. Creatine riboside-high cancer cells were auxotrophic for arginine, revealing a metabolic vulnerability that may be exploited therapeutically. This highlights the potential of creatine riboside not only as a poor prognosis biomarker but also as a companion biomarker to inform the administration of arginine-targeted therapies in precision medicine strategies to improve cancer patient survival.
2022-04-24 | GSE201221 | GEO
Project description:In obesity, misalignment of feeding time with the light/dark environment results in disruption of peripheral circadian clocks. Conversely, restricting feeding to the active period mitigates metabolic syndrome through mechanisms that remain unknown. Here we show that adipocyte thermogenesis is essential for the healthful metabolic response to time restricted feeding. Genetic enhancement of adipocyte thermogenesis through ablation of Zfp423 attenuates obesity caused by circadian mistimed high fat diet feeding through a mechanism involving creatine metabolism. Circadian control of adipocyte creatine metabolism underlies timing of diet-induced thermogenesis, and enhancement of adipocyte circadian rhythms through overexpression of the clock activator Bmal1 ameliorates metabolic complications during diet induced obesity. These findings establish creatine mediated diet-induced thermogenesis as a bioenergetic mechanism driving metabolic benefits during time-restricted feeding.
2022-10-24 | GSE181443 | GEO
Project description:GATM-Mediated Creatine Biosynthesis Enables Maintenance of FLT3-ITD-Mutant Acute Myeloid Leukemia
| PRJNA752603 | ENA
Project description:Obesity is a risk factor for postmenopausal ERα (+) breast cancer. Molecular mechanisms activated by the factors from serum that contribute to this risk and how these mechanisms affect ERα signaling are yet to be elucidated. To identify such mechanisms, we performed whole metabolite and protein profiling in serum samples, which enabled us to focus on factors that were differentially present in serum from cancer-free vs. breast cancer susceptible and obese vs. non-obese post-menopausal women. These studies combined with in vitro assays identified free fatty acids (FFAs), as serum factors that correlate with increased proliferation and aggressiveness in ERα(+) breast cancer cells by. FFAs activated both ERα and mTOR pathways and rewired metabolism in breast cancer cells. Pathway preferential estrogen-1 (PaPE-1), which target ERα and mTOR signaling, was able to block changes induced by FFAs. In fact, PaPEs were more effective in the presence of FFAs, suggesting a role for obesity-associated gene and metabolic rewiring in providing new targetable vulnerabilities for ERα-(+) breast cancer in postmenopausal women. Our findings provide a basis for preventing or inhibiting obesity-associated breast cancer by using PaPEs that would reverse these newly appreciated metabolic properties of breast tumors in obese postmenopausal women.
2019-05-11 | GSE114372 | GEO
Project description:Increased phosphocreatine/creatine ratio in white adipocytes promotes inflammation
| PRJNA791244 | ENA
Project description:Adaptive thermogenesis has attracted much attention because of its ability to raise systemic energy expenditure and counter obesity and diabetes. Recent data have indicated that thermogenic fat cells utilize creatine to stimulate futile substrate cycling, dissipating chemical energy as heat. This model was based on the super-stoichiometric relationship between creatine added to mitochondria and O2 consumed, and this project aims at providing direct evidence for the molecular basis of this futile creatine cycling activity. In this project, we found that thermogenic fat cells contain robust phosphocreatine hydrolase (PCr’ase) activity, attributable to tissue-nonspecific alkaline phosphatase (TNAP), which was identified by the quantitative mass spectrometric analysis of a purified mitochondrial protein fraction containing the PCr’ase activity. TNAP hydrolyzes phosphocreatine to initiate a futile cycle of creatine dephosphorylation and phosphorylation; it is localized to mitochondria of thermogenic fat cells, where the futile creatine cycling occurs. Furthermore, we demonstrated in this project the essential role of TNAP in activating the futile creatine cycling and increasing whole body energy expenditure using genetic and pharmacological approaches. We also found that the genetic depletion of TNAP in murine adipose tissue causes rapid-onset obesity, with no change in movement or feeding behavior of the animals. Using quantitative mass spectrometry, we showed that genetic depletion of TNAP causes an upregulation of UCP1, as well as other proteins involved in oxidative metabolism, to compensate for a dampened thermogenesis. In summary, the data we acquired in this project illustrate the critical role of TNAP as a phosphocreatine phosphatase in the futile creatine cycling and adipose thermogenesis.
2022-02-17 | PXD025032 | Pride