Identification of fatty acid amide hydrolase as a metastasis suppressor in breast cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA813232 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18246763_1.fastq.gz | Fastqsanger.gz | |||
| SRR18246763_2.fastq.gz | Fastqsanger.gz | |||
| SRR18246764_1.fastq.gz | Fastqsanger.gz | |||
| SRR18246764_2.fastq.gz | Fastqsanger.gz | |||
| SRR18246765_1.fastq.gz | Fastqsanger.gz |
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Project description:Clinical management of breast cancer (BC) metastasis remains an unmet need as it accounts for 90% of BC-associated mortality. Although the luminal subtype, which represents >70% of BC cases, is generally associated with a favorable outcome, it is susceptible to metastatic relapse as late as 15 years after treatment discontinuation. Seeking therapeutic approaches as well as screening tools to properly identify those patients with a higher risk of recurrence is therefore essential. Here, we report that the lipid-degrading enzyme fatty acid amide hydrolase (FAAH) is a predictor of long-term survival in patients with luminal BC, and that it blocks tumor progression and lung metastasis in cell and mouse models of BC. Together, our findings highlight the potential of FAAH as a biomarker with prognostic value in luminal BC and as a therapeutic target in metastatic disease.
2022-03-09 | GSE197984 | GEO
Project description:A human gut Faecalibacterium prausnitzii fatty acid amide hydrolase
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Project description:Resmetirom is a liver-directed, thyroid hormone receptor β (THRβ)-selective agonist approved for treating metabolic-associated steatohepatitis (MASH). While Resmetirom hepatocyte-specific effects are well-established, its impact on other hepatic cells, particularly hepatic stellate cells (HSCs), the main fibrogenic cells, remain unknown. Using animal models, immortalized cell lines, and primary murine and human HSCs, we combined pharmacological treatments with genetic manipulation of THRα and fatty acid amide hydrolase (FAAH) to examine the effects of Resmetirom. Resmetirom ameliorates MASH through actions in both hepatocytes and HSCs. The overexpression of solute carrier organic anion transporter family member 1B1(SLCO1β1) in both cell types increases the efficiency of Resmetirom. THRα expression is higher in HSCs than in hepatocytes in both human and murine cells. Resmetirom attenuates TGF-β1-induced HSC activation via THRα and increased FAAH expression and activity, while their inhibition prevents Resmetirom from reducing fibrotic marker expression and the elevated glycolytic activity typical of activated HSCs. These results uncover an unrecognized mechanism of action for Resmetirom, demonstrating that its antifibrotic efficacy extends beyond hepatocytes to include direct effects on HSCs via THRα and FAAH. These results may support the development of future therapeutic strategies aimed at THRα in HSC, in combination with existing approaches targeting hepatocyte THRβ.
2026-07-20 | GSE334408 | GEO
Project description:Resmetirom ameliorates fibrogenesis in hepatic stellate cells via thyroid hormone receptor alpha-fatty-acid amide hydrolase 1 signaling pathway
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Project description:This study aimed to investigate the overlap between hepatic NAT and the bile acid synthesis to identify additional enzymes involved in NAT synthesis in the liver. We sequenced livers high-fat fed mice the were either wild-type or with a single-amino acid substitution in fatty acid amide hydrolase (FAAH S268D), as described in https://doi.org/10.1073/pnas.1916288116.
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Project description:We determined the gene expression changes by URB597, a fatty acid amide hydrolase inhibitor, treatment.
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Project description:Metastasis remains the leading cause of mortality in lung adenocarcinoma (LUAD), yet the molecular mechanisms driving metastatic progression, particularly to the liver, remain incompletely understood. Metabolic reprogramming has emerged as a hallmark of cancer, but how amino acid transport interfaces with lipid metabolism to regulate metastasis is poorly defined. We integrated bioinformatic analysis of The Cancer Genome Atlas (TCGA) LUAD cohort with in vitro and in vivo functional studies. Weighted gene co-expression network analysis (WGCNA) was performed to identify metastasis-associated modules. SLC7A5 function was evaluated using knockdown approaches in LUAD cell lines, assessed by Western blot, wound healing, Transwell migration assays, and an orthotopic lung cancer mouse model. Mechanistic studies included RNA-seq, targeted fatty acid profiling, BODIPY FL C16 uptake assays, Seahorse FAO analysis, and PPARA luciferase reporter assays. WGCNA identified SLC7A5 as a hub gene within a metastasis-associated transcriptional network, with high expression predicting poor overall survival, disease-free survival, and liver metastasis risk in LUAD patients. SLC7A5 knockdown reversed epithelial-mesenchymal transition (EMT), suppressed cell migration in vitro, and significantly reduced intrapulmonary tumor growth in an orthotopic mouse model. Mechanistically, RNA-seq and metabolomic profiling revealed that SLC7A5 deficiency induced profound reprogramming of fatty acid metabolism, characterized by reduced exogenous fatty acid uptake, paradoxically enhanced fatty acid oxidation (FAO), and consequent intracellular fatty acid depletion. Palmitic acid supplementation rescued the migratory defects caused by SLC7A5 knockdown. Transcription factor enrichment analysis identified PPARA as a downstream effector, and SLC7A5 silencing significantly reduced PPARA expression, transcriptional activity, and the expression of its target genes governing fatty acid uptake, synthesis, and oxidation. CPT1 enzymatic activity was correspondingly diminished. Crucially, PPARA overexpression rescued the migratory defects induced by SLC7A5 knockdown, establishing PPARA as a critical functional mediator. Our study identifies SLC7A5 as a key regulator of LUAD metastasis through PPARA-mediated control of fatty acid metabolism, revealing an unexpected metabolic axis linking amino acid transport to lipid homeostasis. These findings establish SLC7A5 as a promising prognostic biomarker and therapeutic target for metastatic LUAD, particularly for patients at high risk of liver metastasis.
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Project description:Benson2014 - FAAH inhibitors for the treatment of osteoarthritic pain
Evaluation of fatty acid amide hydrolase (FAAH) as a target for osteoarthritic pain in humans, using an integrated systems pharmacology model.
The SBML version of the model is obtained from the supplementary material of the corresponding paper (see below).
This model is described in the article:
A systems pharmacology perspective on the clinical development of Fatty Acid amide hydrolase inhibitors for pain.
Benson N, Metelkin E, Demin O, Li GL, Nichols D, van der Graaf PH.
CPT Pharmacometrics Syst Pharmacol. 2014 Jan 15;3:e91.
Abstract:
The level of the endocannabinoid anandamide is controlled by fatty acid amide hydrolase (FAAH). In 2011, PF-04457845, an irreversible inhibitor of FAAH, was progressed to phase II clinical trials for osteoarthritic pain. This article discusses a prospective, integrated systems pharmacology model evaluation of FAAH as a target for pain in humans, using physiologically based pharmacokinetic and systems biology approaches. The model integrated physiological compartments; endocannabinoid production, degradation, and disposition data; PF-04457845 pharmacokinetics and pharmacodynamics, and cannabinoid receptor CB1-binding kinetics. The modeling identified clear gaps in our understanding and highlighted key risks going forward, in particular relating to whether methods are in place to demonstrate target engagement and pharmacological effect. The value of this modeling exercise will be discussed in detail and in the context of the clinical phase II data, together with recommendations to enable optimal future evaluation of FAAH inhibitors.
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2024-09-02 | BIOMD0000000512 | BioModels
Project description:Targeting metastasis stem cells through the fatty acid receptor CD36
| PRJNA295964 | ENA