Cancer-cell-secreted miR-204-5p induces leptin signaling pathway in white adipose tissue to promote cancer-associated cachexia
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA999655 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25447982.fastq.gz | Fastqsanger.gz | |||
| SRR25447983.fastq.gz | Fastqsanger.gz |
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Project description:Cachexia is a wasting disorder of adipose tissues that leads to profound weight loss and frailty. One key characteristic of cachexia is elevated resting energy expenditure, which has been linked to increased fat lipolysis and thermogenesis.
2024-07-23 | GSE239524 | GEO
Project description:Cachexia is a wasting disorder of adipose tissues that leads to profound weight loss and frailty. One key characteristic of cachexia is elevated resting energy expenditure, which has been linked to increased fat lipolysis and thermogenesis. Extracellular vesicles (EVs) are serving as new messengers to mediate cell-cell communication in vivo. How tumors induce brown fat activity is unknown. Here, we found that breast cancer increased hypoxia inducible factor 1 subunit alpha (HIF1A) protein modification through extracellular-vesicle-encapsulated miR-204 targeting von Hippel-Lindau tumor suppressor (VHL), plays an important role in wasting by driving lipolysis and thermogenic gene expression in adipose tissues.
2023-07-13 | GSE222380 | GEO
Project description:Cancer-associated cachexia is a multi-organ weight loss syndrome, especially with a wasting disorder of adipose tissue and skeletal muscle. Small extracellular vesicles (sEVs) serve as emerging messengers to connect primary tumour and metabolic organs to exert systemic regulation. However, whether and how tumour-derived sEVs regulate white adipose tissue (WAT) browning and fat loss is poorly defined. Here, we report breast cancer cell-secreted exosomal miR-204-5p induces hypoxia-inducible factor 1A (HIF1A) in WAT by targeting von Hippel-Lindau (VHL) gene. Elevated HIF1A protein induces the leptin signalling pathway and thereby enhances lipolysis in WAT. Additionally, exogenous VHL expression blocks the effect of exosomal miR-204-5p on WAT browning. Reduced plasma phosphatidyl ethanolamine level is detected in mice lack of cancer-derived miR-204-5p secretion in vivo. Collectively, our study reveals circulating miR-204-5p induces hypoxia-mediated leptin signalling pathway to promote lipolysis and WAT browning, shedding light on both preventive screenings and early intervention for cancer-associated cachexia.
| S-EPMC10449837 | biostudies-literature
Project description:Tumor-derived exosomal miR-204 enhances white adipose tissue browning to promote cancer associated cachexia
| PRJNA921843 | ENA
Project description:Background Loss of skeletal muscle mass in advanced cancer is recognized as an independent predictor of mortality. Mechanisms involved in this wasting process and parameters for early diagnosis are still lacking. As skeletal muscle is considered as a secretory organ, the aim of this present experimental work was to characterize the changes in muscle proteome and secretome associated with cancer-induced cachexia to better understand cellular mechanisms involved in this wasting process and to identify secreted proteins which might reflect the ongoing muscle atrophy process. Methods We investigated first the changes in the muscle proteome associated with cancer-induced cachexia by using differential label-free proteomic analysis on muscle of the C26 mouse model. The differentially abundant proteins were submitted to sequential bioinformatic secretomic analysis in order to identify potentially secreted proteins. Selected reaction monitoring and Western blotting were used to verify the presence of candidate proteins at the circulating level. Their muscle source was demonstrated by assessing their gene expression in skeletal muscle and in cultured myotubes. Finally, we also investigated their regulation in muscle cells. Alterations in several molecular pathways potentially involved in muscle atrophy were highlighted using Gene ontology enrichment analyses. Results Our results revealed a dramatic increased production (2-to 25-fold) by the muscle of several acute phase reactants (APR: Haptoglobin, Serpina3n, Complement C3, Serum amyloid A1) which are also released in the circulation during C26 cancer cachexia. Their production was confirmed in other preclinical models of cancer cachexia as well as in cancer patients. The muscular origin of these APR was demonstrated by their increased expression in skeletal muscle and myotubes. Glucocorticoids and pro-inflammatory cytokines contribute directly to their increased expression in muscle cells in vitro, while the role of IL-6 in the muscular induction of these APR was demonstrated in vivo. Conclusions Cancer is associated with marked changes in muscle secretome during muscle wasting. Our study demonstrates a marked increased production of APR by skeletal muscle in pre-clinical models of cancer cachexia and in cancer patients. Further studies are required to unravel the potential role of these proteins in muscle atrophy and their interest as biomarkers of cancer cachexia.
2020-10-28 | PXD016474 | Pride
Project description:Cachexia, a severe wasting syndrome characterized by tumor-induced metabolic dysregulation, is a leading cause of death in cancer patients, yet its underlying mechanisms remain poorly understood. We performed a longitudinal full-body single-nuclei resolution transcriptome analysis in a Drosophila model of cancer cachexia to capture interorgan dysregulations. Our study revealed that the tumor-secreted interleukin-like cytokine Upd3 induces fat body expression of Pepck1 and Pdk, key regulators of gluconeogenesis, disrupting glucose metabolism and contributing to cachexia. Similarly, in mouse cancer cachexia models, we observe regulation of their orthologs Pck1 and Pdk3 by IL-6/JAK-STAT signaling. Elevated expression of these genes in fly, mouse, and patients correlates with poor prognosis, and hepatic expression of Pdk3 emerges as a novel mechanism contributing to metabolic dysfunction in cancer cachexia. This study highlights the conserved nature of tumor-induced metabolic disruptions and identifies new therapeutic targets to mitigate cachexia in cancer patients.
2025-02-13 | GSE286259 | GEO
Project description:Cancer cachexia with profound weight loss and frailty impairs quality of life, limits cancer therapy and decreases survival, against which no effective therapy is available. Dkk1 is a secreted antagonist of Wnt/β-catenin pathway via interacting with Wnt co-receptors LRP5 and 6 (LRP5/6) and inducing their endocytosis1-4. Although Dkk1 is critical for animal development3,5, its mRNA is undetectable in most adult organs6. Of note, elevated circulating Dkk1 leads to poor prognosis in patients with a variety of types of cancer by a completely unknown mechanism. Here, we show that administration of a recombinant Dkk1 protein accelerated cancer cachexia-related death through inducing LRP6 endocytosis but not β-catenin inhibition, whereas pharmacological blockade of Dkk1-induced membrane LRP6 downregulation completely prevented cancer cachexia and robustly prolonged survival in tumor-bearing mice. Pharmacological blockade of Dkk1-induced membrane LRP6 downregulation prevented alterations of a number of GPCR pathways and all main cancer cachexia-related pathways in skeletal muscle of mice bearing tumor as shown by a genome-wide transcriptional analysis. Furthermore, Dkk1 injection into hindlimb directly triggered activations of GPCR pathways and cachexia-related pathways. These findings establish a key role of the Dkk1-LRP6 axis in cancer cachexia development through affecting GPCR pathways and suggest a highly promising therapeutic approach for preventing cancer cachexia.
2024-12-01 | GSE121873 | 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:Cachexia is a wasting syndrome characterized by pronounced skeletal muscle loss. In cancer, cachexia associates with increased morbidity and mortality and decreased treatment tolerance. Although advances have been made in understanding the mechanisms of cachexia, translating these advances to the clinic has been challenging. One reason for this shortcoming may be the current animal models that fail to fully recapitulate the etiology of human cancer-induced tissue wasting. Because pancreatic ductal adenocarcinoma (PDA) presents with a high incidence of cachexia, we engineered a mouse model of PDA, that we named KPP. KPP mice, similar to PDA patients, progressively lose skeletal and adipose mass as a consequence of their tumors. In addition, KPP muscles exhibit a similar gene ontology to cachectic patients. We envision the KPP model will be a useful resource for advancing our mechanistic understanding and ability to treat cancer cachexia.
2019-08-06 | GSE133524 | GEO
Project description:Cachexia is a wasting syndrome characterized by pronounced skeletal muscle loss. In cancer, cachexia associates with increased morbidity and mortality and decreased treatment tolerance. Although advances have been made in understanding the mechanisms of cachexia, translating these advances to the clinic has been challenging. One reason for this shortcoming may be the current animal models that fail to fully recapitulate the etiology of human cancer-induced tissue wasting. Because pancreatic ductal adenocarcinoma (PDA) presents with a high incidence of cachexia, we engineered a mouse model of PDA, that we named KPP. KPP mice, similar to PDA patients, progressively lose skeletal and adipose mass as a consequence of their tumors. In addition, KPP muscles exhibit a similar gene ontology to cachectic patients. We envision the KPP model will be a useful resource for advancing our mechanistic understanding and ability to treat cancer cachexia.
2019-08-06 | GSE133523 | GEO