PLA2 driven lipid remodelling in ARMS tumorigenic cells
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ABSTRACT:
PROVIDER: PRJNA1256491 | ENA |
REPOSITORIES: ENA
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Project description:Alveolar rhabdomyosarcoma (ARMS) is an aggressive pediatric soft tissue sarcoma with poor relapse-free survival, especially in metastatic cases. Tumor-initiating cells (TICs) are implicated in recurrence and therapy resistance in ARMS, but their metabolic adaptations remain poorly understood. Emerging evidence suggests that lipid metabolism supports stem-like properties in cancer, yet the role of lipid remodeling enzymes in TIC function has not been defined. Here, we investigate the transcriptomic and metabolic profiles of ARMS TICs using tumorsphere-derived and adherent cells from cell line and patient-derived xenograft models. Gene expression and lipid species differences were analyzed using RNA sequencing, gene set enrichment analysis, qPCR, and mass spectrometry. Lipid droplet accumulation was assessed using Oil Red O and BODIPY staining, and functional dependence on PLA2 activity was evaluated using Darapladib. Seahorse assays were used to examine glycolytic and mitochondrial flux, and in vitro and in vivo assays assessed tumorsphere formation, migration, and tumorigenicity. We found that tumorspheres exhibited upregulation of lipid metabolism, especially multiple PLA2 isoforms, and downregulation of glycolytic gene expression. Lipidomic profiling revealed enrichment of linoleic acid-derived triglycerides and lysophospholipids, alongside increased PLA2 activity. Tumorspheres accumulated lipid droplets and upregulated lipid storage regulators PPARG and CD36. Inhibition of PLA2 with Darapladib impaired TIC self-renewal, migration, and in vivo tumor growth, without affecting mouse body weight. These effects were rescued by exogenous linoleic acid supplementation, implicating PLA2-mediated lipid signaling in TIC maintenance. Despite suppressed glycolysis and partial sensitivity to fatty acid oxidation blockade, TICs remained functionally intact under metabolic stress, demonstrating high metabolic flexibility. Collectively, these findings identify PLA2-driven lipid remodeling as a key metabolic adaptation in ARMS TICs that supports stem-like function independently of canonical energy pathways, highlighting PLA2 as a promising therapeutic target in pediatric sarcomas.
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Project description:We analyzed the expression signatures of 10 tumor biopsies from children affected by alveolar rhabdomyosarcoma (ARMS) to identify genes correlating to biological features of this tumor. Five of these patients were positive for the PAX3-FKHR fusion gene and five were negative. We used a cDNA platform containing a large majority of probes derived for muscle tissues. The comparison of transcription profiles of tumor samples with normal fetal skeletal muscle identified 171 differentially expressed genes common to all ARMS patients. The functional analysis of altered genes led to the identification of a group of transcripts (BCOR, DDX5, LGALS1, BIN1) that may be relevant for the tumorigenic processes leading a normal muscle cell to become a malignant rhabdomyoblast. The muscle-specific platform was able to distinguish PAX3-FKHR positive and negative ARMS through the expression pattern of a limited number of genes (RAC1, CFL1, CCND1) that might be biologically relevant for the different clinical behavior and aggressiveness of the two ARMS subtypes. Expression levels for selected candidate genes were validated by quantitative real-time reverse-transcription PCR. Keywords: human fetal skeletal muscle, alveolar rhabdomyiosarcoma, gene expression profiling, PAX3-FKHR
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Project description:Background: Increased proliferation of airway smooth muscle (ASM) cells leading to hyperplasia and increased ASM mass is one of the most characteristic features of airway remodelling in asthma. A bioactive lipid, sphingosine-1-phosphate (S1P), has been suggested to affect airway remodelling by stimulation of human ASM cell proliferation. Objective: To investigate the effect of S1P on signalling and regulation of gene expression in ASM cells from healthy and asthmatic individuals. Methods: ASM cells grown from bronchial biopsies of healthy and asthmatic individuals were exposed to S1P. Gene expression was analysed using microarray, real-time PCR and western blotting. Receptor signalling and function was determined by mRNA knockdown and intracellular calcium mobilisation experiments. Results: S1P potently regulated the expression of more than 80 genes in human ASM cells, including several genes known to be involved in the regulation of cell proliferation and airway remodelling (HBEGF, TGFB3, TXNIP, PLAUR, SERPINE1, RGS4). S1P acting through S1P2 and S1P3 receptors activated intracellular calcium mobilisation and extracellular signal-regulated and Rho-associated kinases to regulate gene expression. S1P-induced responses were not inhibited by corticosteroids and did not differ significantly between ASM cells from healthy and asthmatic individuals. Conclusion: S1P induces a steroid-resistant, pro-remodelling pathway in ASM cells. Targeting S1P or its receptors could be a novel treatment strategy for inhibiting airway remodelling in asthma. Airway smooth muscle cells from 3 healthy donors were cultured and stimulated for 4 h with sphingosine-1-phosphate (100 nM) or medium control. Total RNA was extracted and analysed using Affymetrix Human Exon 1.0 ST arrays.
2015-06-18 | E-GEOD-58657 | biostudies-arrayexpress