The Time-Course of Cancer Cachexia Onset Reveals Biphasic Transcriptional Disruptions in Female Skeletal Muscle Distinct from Males
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE222317 | GEO | 2023/06/29
REPOSITORIES: GEO
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Project description:Background: Cancer cachexia (CAC) reduces patient survival and quality of life. Developments of efficient therapeutic strategies are required for the CAC treatments. This long-term process could be shortened by the drug-repositioning approach which exploits old drugs approved for non-cachexia disease. Amiloride, a diuretic drug, is clinically used for treatments of hypertension and edema due to heart failure. Here, we explored the effects of amiloride for ameliorating muscle wasting in murine models of cancer cachexia. Methods: CT26 and LLC tumor cells were subcutaneously injected into mice to induce cancer cachexia. Amiloride was intraperitoneally injected daily once tumors were formed. Cachexia features of the CT26 and LLC models, respectively, were characterized by phenotypic, histopathologic and biochemical analyses. Plasma exosomes and muscle atrophy-related proteins were quantitatively analyzed. Integrative NMR-based metabolomic and transcriptomic analyses were conducted to identify significantly altered metabolic pathways and distinctly changed metabolism-related biological processes in gastrocnemius. Results: The CT26 and LLC models displayed prominent cachexia features including decreases in body weight, skeletal muscle, adipose tissue and muscle strength. The amiloride treatment in tumor-bearing mice distinctly alleviated muscle atrophy and relieved cachexia-related features without affecting tumor growth. The CT26 and LLC cachexia mice showed increased particle density of plasma exosomes which were largely derived from tumors. Significantly, the amiloride treatment inhibited tumor-derived exosome release, which did not obviously affect exosome secretion from non-neoplastic tissues or induce observable systemic toxicities in normal healthy mice. Integrative-omics revealed significant metabolic impairments in cachectic gastrocnemius, including promoted muscular catabolism, inhibited muscular protein synthesis, blocked glycolysis and impeded ketone body oxidation. The amiloride treatment evidently improved the metabolic impairments in cachectic gastrocnemius. Conclusions: Our results demonstrated the efficacy of amiloride in ameliorating cachectic muscle wasting and elucidated the underlying mechanistic rationale for its use as an alternative strategy to improve CAC treatments.
2021-07-14 | GSE173250 | GEO
Project description:Cancer cachexia is a metabolic syndrome with alterations in gene expression profile that consequently lead to skeletal muscle wasting. Here, we used RNA sequencing to analyze the mRNA expression profile in the tibialis anterior muscles of the Lewis lung carcinoma (LLC) model of cancer cachexia.
2020-05-19 | GSE144567 | GEO
Project description:Cancer cachexia is a metabolic syndrome with alterations in gene expression profile that consequently lead to skeletal muscle wasting. Here, we used RNA sequencing to analyze the microRNA expression profile in the tibialis anterior muscles of the Lewis lung carcinoma (LLC) model of cancer cachexia.
2020-05-19 | GSE145393 | GEO
Project description:Cachexia frequently develops in patients with pancreatic ductal adenocarcinoma (PDAC) and contributes to cancer deaths.Sex differences have been observed in cancer cachexia; however, the underlying molecular mechanisms are far less addressed. We assessed sex difference in PDAC cachexia phenotypes in the KPC (Kras-G12D;Trp-R172H;Pdx1::Cre) genetically engineered mouse model of PDAC and profiled gene expression in the quadriceps skeletal muscles. Males with PDAC experienced earlier cachexia-onset than the female counterpart and activin blockade by ACVR2B/Fc reduced cachexia sympotomes in males but not females. PDAC induced earlier global transcritome alterations in males than females.
2022-05-10 | GSE157251 | GEO
Project description:The mechanisms underlying exercise-induced effects in the skeletal muscle during cancer cachexia progression have not been fully described. Here, we tested the hypothesis that different exercise training protocols could attenuate metabolic impairment in a severe model of cancer cachexia. Moderate-intensity training (MIT) and high-intensity interval training (HIIT) improved running capacity and prolonged lifespan in tumor-bearing rats. HIIT also reduced oxidative stress and reestablished muscle contractile function. An unbiased proteomics screening revealed that COP9 signalosome complex subunit 2 (COPS2), also known as thyroid receptor interacting protein 15 (TRIP15) or ALIEN, is one of the most downregulated proteins at the early stage of cancer cachexia progression. HIIT restored COPS2/TRIP15/ALIEN protein expression to the control levels. Moreover, lung cancer patients with low endurance capacity had lower muscle COPS2/TRIP15/ALIEN protein content compared to age- and sex-matched control subjects. We further established an in vitro model of cancer-induced muscle wasting using tumor cells-conditioned media to explore the potential protective role of COPS2/TRIP15/ALIEN for myotubes homeostasis. This in vitro model indicate that tumor cells produce factors that directly affect myotube metabolism, but COPS2/TRIP15/ALIEN overexpression is not able to fully reestablish metabolic homeostasis and protein content in myotubes incubated with tumor cells-conditioned media. The current study provides new insight into the role of exercise training as a co-therapy for cancer cachexia and uncovers COPS2/TRIP15/ALIEN as a novel potential target for cancer cachexia.
2021-09-08 | PXD013226 | Pride
Project description:Skeletal muscle transcriptome profile in LLC mice model of cancer cachexia.
| PRJNA604025 | ENA
Project description:Cancer cachexia (CC) is a poorly understood cause of morbidity and mortality, which has no efficacious treatment or generally-accepted management strategy. The consensus definition for CC identified skeletal muscle loss as a key marker in the diagnosis and classification of cachexia. The importance of fat wasting however, is less understood. During cachexia, different adipose depots demonstrate differential wasting rates. Studies from animal models have suggested adipose tissue may be a key driver of muscle wasting through fat-muscle crosstalk but human studies in this area are lacking. We performed global gene expression profiling of intra-abdominal (IAAT) and subcutaneous (SAT) adipose from weight stable and cachectic cancer patients and healthy controls. Cachexia was defined as >2% weight loss plus low CT-muscularity. Biopsies of SAT and IAAT were taken from patients undergoing resection for oesophago-gastric cancer, and healthy controls (donor nephrectomy) (n=16 and 8 respectively). RNA was isolated and reverse transcribed. cDNA was hybridised to the Affymetrix Clariom S Microarray and data was analysed using R/Bioconductor. Differential expression of genes was assessed using empirical Bayes and moderated-t-statistic approaches. Category enrichment analysis was used with a tissue-specific background to examine the biological context of differentially expressed genes. Selected differentially regulated genes were validated by qPCR. ELISA for Intelectin-1 was performed on IAAT samples for the corresponding patients. The current cohort plus 12 additional patients from each group also had plasma Intelectin-1 ELISA carried out. In IAAT versus SAT comparisons there were 2101, 1722 and 1659 significantly regulated genes in the cachectic, weight stable and control groups respectively. There were 2200 significantly regulated genes from IAAT in cachectic patients compared to controls and 1253 significantly regulated genes from IAAT in weight stable cancer patients compared to controls. The gene showing the largest difference in expression was Intelectin-1 (Omentin-1) (FDR corrected p=0.0001); a novel adipocytokine associated with weight loss in other groups. Genes involving inflammation were enriched in cancer and control IAAT versus SAT though different groups of genes contributed. Energy metabolism and fat browning genesets were downregulated in cancer IAAT as were key fat browning genes (e.g. UCP1). SAT and IAAT have unique gene expression signatures. IAAT is metabolically active in cancer, and maybe a target for therapeutic manipulation. IAAT may play a fundamental role in cachexia, but the downregulation of energy metabolism genes implies a limited role for fat browning in human cachectic patients, in contrast to pre-clinical models.
2020-05-29 | GSE131835 | GEO
Project description:Pancreatic cancer is characterized by a high frequency of cachexia, pain and neural invasion (N-inv). Neural damage is occurred by N-inv and modulates pain and muscle atrophy via the activation of astrocyte in the connected spine. The activated astrocyte by N-inv, thus, may affect cachexia in pancreatic cancer. Clinical studies in patients and autopsy cases with pancreatic cancer have revealed that N-inv is related to cachexia and astrocytic activation. We established a novel murine model of cancer cachexia using N-inv of human pancreatic cancer cells. Mice with N-inv showed a loss of body weight, skeletal muscle, and fat mass without appetite loss, which are compatible with an animal model of cancer cachexia. Activation of astrocytes in the spinal cord connected with N-inv was observed in our model. Experimental cachexia was suppressed by disrupting neural routes or inhibiting the activation of astrocytes. These data provide the first evidence that N-inv induces cachexia via astrocytic activation of neural route in pancreatic cancer. We produced neural invasion (N-inv) model using intraneural injection of Capan-1 cells to left sciatic nerve of male SCID mouse. For controls, subcutaneous model (SC) and PBS model were produced. Microarray analysis was performed using the first lumbar cord (L1) from PBS, SC, and N-inv mice at 6 w (n = 2 each).
2011-12-07 | E-GEOD-34189 | biostudies-arrayexpress
Project description:The regulatory gene pathways underlying the loss of adipose tissue in cancer cachexia are unknown and were explored using pangenomic transcriptome profiling. Gene expression profiles (Human Gene 1.0 ST) of abdominal subcutaneous adipose tissue were studied in gastrointestinal cancer patients with (N=13) or without (N=14) cachexia. Data analyses were performed using the Affymetrix GeneChip Operating Software (GCOS) Version 1.4.
2010-04-10 | E-GEOD-20571 | biostudies-arrayexpress
Project description:Skeletal muscle transcriptome profile in LLC mice model of cancer cachexia [miRNA-seq]
| PRJNA607068 | ENA