Development of a peptide drug restoring AMPK and adipose tissue functionality in cancer cachexia
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA988064 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25040733_1.fastq.gz | Fastqsanger.gz | |||
| SRR25040733_2.fastq.gz | Fastqsanger.gz | |||
| SRR25040734_1.fastq.gz | Fastqsanger.gz | |||
| SRR25040734_2.fastq.gz | Fastqsanger.gz | |||
| SRR25040735_1.fastq.gz | Fastqsanger.gz |
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Project description:Cancer cachexia is a severe systemic wasting disease that negatively affects quality of life and survival in patients with cancer. To date, treating cancer cachexia is still a major unmet clinical need. We recently discovered the destabilization of the AMPK complex in adipose tissue as a key event in cachexia-related adipose tissue dysfunction and developed an AAV-based approach to prevent AMPK degradation and prolong cachexia-free survival. Here, we show the development and optimization of a prototypic peptide, Pen-X-ACIP, where the AMPK stabilizing peptide ACIP is fused to the cell-penetrating peptide moiety penetratin via a propargylic glycine linker to enable late-stage functionalization using click chemistry. Pen-X-ACIP was efficiently taken up by adipocytes, inhibited lipolysis and restored AMPK signaling. Tissue uptake assays showed a favorable uptake profile into adipose tissue upon intraperitoneal injection. Systemic delivery of Pen-X-ACIP into tumor-bearing animals prevented the progression of cancer cachexia without affecting tumor growth, and preserved body weight and adipose tissue mass with no discernable side effects in other peripheral organs, thereby achieving proof-of-concept. As Pen-X-ACIP also exerted its anti-lipolytic activity in human adipocytes, it now provides a promising platform for further (pre)clinical development towards a novel, first-in-class approach against cancer cachexia.
2023-07-02 | GSE235940 | GEO
Project description:Cancer cachexia is a severe systemic wasting disease that negatively affects quality of life and survival in patients with cancer. To date, treating cancer cachexia is still a major unmet clinical need. We recently discovered the destabilization of the AMP-activated protein kinase (AMPK) complex in adipose tissue as a key event in cachexia-related adipose tissue dysfunction and developed an adeno-associated virus (AAV)-based approach to prevent AMPK degradation and prolong cachexia-free survival. Here, we show the development and optimization of a prototypic peptide, Pen-X-ACIP, where the AMPK-stabilizing peptide ACIP is fused to the cell-penetrating peptide moiety penetratin via a propargylic glycine linker to enable late-stage functionalization using click chemistry. Pen-X-ACIP was efficiently taken up by adipocytes, inhibited lipolysis, and restored AMPK signaling. Tissue uptake assays showed a favorable uptake profile into adipose tissue upon intraperitoneal injection. Systemic delivery of Pen-X-ACIP into tumor-bearing animals prevented the progression of cancer cachexia without affecting tumor growth and preserved body weight and adipose tissue mass with no discernable side effects in other peripheral organs, thereby achieving proof of concept. As Pen-X-ACIP also exerted its anti-lipolytic activity in human adipocytes, it now provides a promising platform for further (pre)clinical development toward a novel, first-in-class approach against cancer cachexia.
| S-EPMC10422018 | biostudies-literature
Project description:Blocking ActRIIB signaling and restoring appetite reverses cachexia and improves survival in mice with lung cancer
| PRJNA698354 | ENA
Project description:Cancer cachexia is a common, debilitating condition with limited therapeutic options. The defining feature of cachexia is weight loss, which suggests a state of negative energy balance. Using an established genetically engineered mouse model of lung cancer, we found that cachexia is characterized by reduced food intake, spontaneous activity, and energy expenditure accompanied by muscle metabolic dysfunction and atrophy. Calorie restriction in wild-type mice does not recapitulate this phenotype, suggesting that reduced food intake is not the only driver of weight loss in this model. Using unbiased RNA-sequencing of the muscle and tumor, we identified Activin A as a purported driver of the peripheral metabolic dysfunction. To reverse anorexia and muscle dysfunction, we treated the mice with anamorelin (Ana), a ghrelin receptor agonist, alone or in combination with the ActRIIB-Fc, a decoy ligand for TGF-β/activin family members. Ana effectively increased food intake but only the combination of drugs increased lean mass, restored spontaneous activity, and improved overall survival. These beneficial effects were limited to female mice and were dependent on ovarian function. In agreement, we found that high expression of Activin A in human lung adenocarcinoma correlates with unfavorable prognosis only in female patients, even though expression levels are similar in both sexes. Overall, our study suggests that multimodal, sex-specific, therapies are needed to reverse CACS.
2022-07-09 | GSE165856 | GEO
Project description:In order to screen miRNAs related to cachexia, we collected plasma from patients with gastric cancer cachexia or without cachexia, and extracted exosomes from plasma. Then, we analyzed the gene expression profile of 3 gastric cancer patients with cachexia and 2 gastric cancer patients with non cachexia.
2024-12-23 | GSE221666 | 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 | GSE133523 | 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 | GSE133524 | GEO
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:Cachexia is an exacerbating event in many types of cancer that is strongly associated with a poor prognosis. We have identified cytokine, signaling and transcription factors that are required for cachexia in the mouse C26 colon carcinoma model of cancer. C2C12 myotubes treated with conditioned medium from C26 cancer cells induced atrophy and activated a STAT-dependent reporter gene but not reporter genes dependent on SMAD, FOXO, C/EBP, NF-ĸB, or AP-1. Of the gp130 family members IL-11, IL-6, oncostatin M (OSM), and leukemia inhibitory factor (LIF), only OSM and LIF were sufficient to activate the STAT reporter in myotubes. A LIF blocking antibody abolished C26 CM-induced STAT reporter activation STAT3 phosphorylation and myotube atrophy, but blocking antibodies to IL-6 or OSM did not. JAK2 inhibitors also blocked the C26 CM-induced STAT reporter activation, STAT3 phosphorylation, and atrophy in myotubes. LIF at levels found in the C26 CM was sufficient for STAT reporter activation and atrophy in myotubes. In vivo, an increase in serum LIF preceded the increase in IL-6 in mice with C26 tumors. Overexpression of a dominant negative Stat3Cβ-EGFP gene in myotubes and in mouse muscle blocked the atrophy caused by C26 CM or C26 tumors, respectively. Taken together these data support an important role of LIF- JAK2-STAT3 in C26 cachexia and point to a therapeutic approach for at least some types of cancer cachexia. from three replicate wells of cells at each treatment, pools of total RNA were used to create cDNA which were evaluated on Affymetrix mouse gene 1.0 ST v.1 arrays.
2015-06-25 | E-GEOD-68827 | biostudies-arrayexpress