GDF15 neutralization restores muscle function and physical performance in a mouse model of cancer cachexia
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA886080 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21776634_1.fastq.gz | Fastqsanger.gz | |||
| SRR21776634_2.fastq.gz | Fastqsanger.gz | |||
| SRR21776635_1.fastq.gz | Fastqsanger.gz | |||
| SRR21776635_2.fastq.gz | Fastqsanger.gz | |||
| SRR21776636_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 78 |
Similar Datasets
Project description:Cancer cachexia is a disorder characterized by both involuntary weight loss and impaired physical performance. Decline in physical performance of patients with cachexia is associated with poor quality of life, and currently there are no effective pharmacological interventions that restore physical performance. Here we examined the effect of GDF15 neutralization in a mouse model of cancer-induced cachexia (TOV21G) that manifested weight loss and muscle function impairments. With comprehensive assessments, our results demonstrated that cachectic mice treated with the anti-GDF15 antibody mAB2 exhibited body weight gain with near-complete restoration of muscle mass and markedly improved muscle function and physical performance. Mechanistically, the improvements induced by GDF15 neutralization were primarily attributed to increased caloric intake, while altered gene expressions in cachectic muscles were restored in both caloric intake-dependent and -independent manners. The findings implicate the potential of GDF15 neutralization as an effective therapy to enhance physical performance of patients with cachexia.
2023-01-11 | GSE214603 | GEO
Project description:Heart failure and associated cachexia is an unresolved and important problem. We report a new model of severe heart failure that consistently results in cachexia. Mice lacking the integrated stress response (ISR) induced eIF2α phosphatase, PPP1R15A, exhibit a dilated cardiomyopathy and severe weight loss following irradiation, whilst wildtype mice are unaffected. This is associated with increased expression of Gdf15 in the heart and increased levels of GDF15 in the circulation. We provide evidence that blockade of GDF15 activity prevents cachexia and slows the progression of heart failure. Our data suggests that cardiac stress mediates a GDF15 dependent pathway that drives weight loss and worsens cardiac function. We show relevance of GDF15 to lean mass and protein intake with patients with heart failure. Blockade of GDF15 could constitute a novel therapeutic option to limit cardiac cachexia and improve clinical outcomes in patients with severe systolic heart failure.
2024-07-30 | E-MTAB-12831 | biostudies-arrayexpress
Project description:Elevation of growth differentiation factor 15 (GDF15) has recently emerged as a key driver of cancer cachexia, a syndrome of extreme weight loss that affects patients with various types of cancer. Chemotherapy, as well as the tumour itself have been reported to contribute to increased GDF15 secretion in both cancer and host tissues. Bromodomain and extraterminal (BET) domain proteins have been shown to regulate GDF15 expression in pancreatic cancer cells. With currently neither preventive strategies nor specific therapeutic options for cachexia available, antibodies targeting GDF15 or its receptor are being developed. However, the mechanism of chemotherapy-induced GDF15 upregulation in tumour and host cells is still unknown, leaving uncertainty about safety and efficacy of therapies targeting retrospective reduction of GDF15 in cancer cachexia. We tested various cardiotoxic drugs for their effect on GDF15 regulation in cardiomyocyte cell culture and analysed gene expression, mutational status, and pathway activities of the NCI-60 cancer cell line panels to get further insights into the regulation of GDF15 expression in both cancer and host cells upon treatment with anticancer drugs. To investigate the regulatory effect of BET inhibition on GDF expression more extensively, we screened BET inhibitors in doxorubicin treated human cardiomyocyte cell culture as well as in 21 cancer cell lines and performed differential analysis of gene expression, metabolites, and pathway activities. Our results reveal that DNA interacting compounds induce GDF15 expression in human cardiomyocytes up to 20-fold, whereas cardiotoxic drugs with other modes of action led, if at all, to less than 3-fold induction. We discovered that BET inhibitors suppress doxorubicin-induced GDF15 overexpression in human cardiomyocytes up to 7.4-fold (p=0.0051). In cancer cell lines, we identified compound-specific gene signatures that correlate with the extent of GDF15 induction upon treatment in the espective cell line. BET inhibition also reduces GDF15 expression in a defined subset of cancer cell lines that differentiate from the other tested cell lines in a less active PI3K/Akt axis and significantly higher extracellular pantothenate concentration (p=0.00095). We identified compound- and cell-line-specific gene signatures that predict GDF15 upregulation upon treatment, providing indication that the risk for drug-induced GDF15 overexpression and concomitant cachexia can be reduced by a biomarker-driven selection of patient-specific anticancer agents. Our results suggest that BET inhibitors could counteract cachexia at the transcriptional level in tumour and host tissues by reducing GDF15 expression. We identified characteristic gene and metabolite expressions of responsive cancer cell lines that can serve as biomarkers for patient selection.
2023-07-07 | GSE210541 | GEO
Project description:Elevation of growth differentiation factor 15 (GDF15) has recently emerged as a key driver of cancer cachexia, a syndrome of extreme weight loss that affects patients with various types of cancer. Chemotherapy, as well as the tumour itself have been reported to contribute to increased GDF15 secretion in both cancer and host tissues. Bromodomain and extraterminal (BET) domain proteins have been shown to regulate GDF15 expression in pancreatic cancer cells. With currently neither preventive strategies nor specific therapeutic options for cachexia available, antibodies targeting GDF15 or its receptor are being developed. However, the mechanism of chemotherapy-induced GDF15 upregulation in tumour and host cells is still unknown, leaving uncertainty about safety and efficacy of therapies targeting retrospective reduction of GDF15 in cancer cachexia. We tested various cardiotoxic drugs for their effect on GDF15 regulation in cardiomyocyte cell culture and analysed gene expression, mutational status, and pathway activities of the NCI-60 cancer cell line panels to get further insights into the regulation of GDF15 expression in both cancer and host cells upon treatment with anticancer drugs. To investigate the regulatory effect of BET inhibition on GDF expression more extensively, we screened BET inhibitors in doxorubicin treated human cardiomyocyte cell culture as well as in 21 cancer cell lines and performed differential analysis of gene expression, metabolites, and pathway activities. Our results reveal that DNA interacting compounds induce GDF15 expression in human cardiomyocytes up to 20-fold, whereas cardiotoxic drugs with other modes of action led, if at all, to less than 3-fold induction. We discovered that BET inhibitors suppress doxorubicin-induced GDF15 overexpression in human cardiomyocytes up to 7.4-fold (p=0.0051). In cancer cell lines, we identified compound-specific gene signatures that correlate with the extent of GDF15 induction upon treatment in the espective cell line. BET inhibition also reduces GDF15 expression in a defined subset of cancer cell lines that differentiate from the other tested cell lines in a less active PI3K/Akt axis and significantly higher extracellular pantothenate concentration (p=0.00095). We identified compound- and cell-line-specific gene signatures that predict GDF15 upregulation upon treatment, providing indication that the risk for drug-induced GDF15 overexpression and concomitant cachexia can be reduced by a biomarker-driven selection of patient-specific anticancer agents. Our results suggest that BET inhibitors could counteract cachexia at the transcriptional level in tumour and host tissues by reducing GDF15 expression. We identified characteristic gene and metabolite expressions of responsive cancer cell lines that can serve as biomarkers for patient selection.
2023-07-07 | GSE210540 | GEO
Project description:GDF15 antagonism limits severe heart failure and prevents cardiac cachexia in mice
| PRJEB61161 | ENA
Project description:GDF15 gene suppression by BET inhibition and gene signature based personalized chemotherapy to counteract cachexia
| PRJNA866126 | ENA
Project description:Growth Differentiation Factor 15 (GDF15) is a divergent member of the TGF-β superfamily, and its expression increases under various stress conditions, including inflammation, hyperoxia, and senescence. GDF15 expression is increased in neonatal murine BPD models, and GDF15 loss exacerbates oxidative stress and decreases viability in vitro in pulmonary epithelial and endothelial cells. Our overall hypothesis is that the loss of GDF15 will exacerbate hyperoxic lung injury in the neonatal lung in vivo. We exposed neonatal Gdf15-/- mice and wild-type (WT) controls on a similar background to room air or hyperoxia (95% O2) for 5 days after birth. The mice were euthanized on PND 21. Gdf15 -/- mice had higher mortality and lower body weight than WT mice after exposure to hyperoxia. Upon exposure to hyperoxia, female mice had higher alveolar simplification in the Gdf15-/- group than the female WT group. Gdf15-/- and WT mice showed no difference in the degree of the arrest in angiogenesis upon exposure to hyperoxia. Gdf15-/- mice showed lower macrophage count in the lungs compared to WT mice. Our results suggest that Gdf15 deficiency decreases the tolerance to hyperoxic lung injury with evidence of sex-specific differences.
2023-07-20 | GSE211744 | GEO
Project description:GDF15 gene suppression by BET inhibition and gene signature based personalized chemotherapy to counteract cachexia [RNA-seq]
| PRJNA866130 | ENA
Project description:GDF15 gene suppression by BET inhibition and gene signature based personalized chemotherapy to counteract cachexia [Quant-seq]
| PRJNA866131 | ENA
Project description:Lifestyle intervention including exercise restores glucose homeostasis and pancreatic β-cell function in type 2 diabetes (T2D). However, exercise compliance is a challenge. Novel alternative or adjuvant approaches are necessary. During exercise, the contracting skeletal muscle acts as endocrine organ via the secretion and endocrine signaling of functional proteins. We postulated that contracting skeletal muscle secretes proteins that target pancreatic β-cells and regulate insulin secretion and glucose metabolism. To test this hypothesis, we used an in vitro cell-based skeletal muscle contraction system to uncover proteins released in the muscle secretome. Using an RNAseq screen, we identified growth differentiation factor 15 (GDF15) as a lead candidate. β-cells, human pancreatic islets, and C57BL/6J mice exposed to acute GDF15 treatment exhibited increased glucose-stimulated insulin secretion, and the mechanism involved activation of the insulin release pathway. Chronic GDF15 treatment in db/db mice reduced insulin resistance and preserved pancreatic PDX-1 expression. Consistently, plasma GDF15 increased concurrently with C-peptide prior to the onset of chronic hyperglycemia in humans with pre-diabetes. In addition, in humans with T2D, exercise-induced GDF15 was associated with enhanced β-cell function. These findings support GDF15 as a potential therapeutic target for type 2 diabetes and associated co-morbidities.
2022-10-31 | GSE139872 | GEO