Related Experiment Video
Updated: Dec 13, 2025
Tumorsphere Derivation and Treatment from Primary Tumor Cells Isolated from Mouse Rhabdomyosarcomas
Published on: September 13, 2019
Characterization of mTOR Activity and Metabolic Profile in Pediatric Rhabdomyosarcoma
Luca Felkai1, Ildikó Krencz2, Dorottya Judit Kiss1
12nd Department of Pediatrics, Semmelweis University, 1094 Budapest, Hungary.
Abstract:
mTOR activation has been observed in rhabdomyosarcoma (RMS); however, mTOR complex (mTORC) 1 inhibition has had limited success thus far. mTOR activation alters the metabolic pathways, which is linked to survival and metastasis. These pathways have not been thoroughly analyzed in RMSs. We performed immunohistochemistry on 65 samples to analyze the expression of mTOR complexes (pmTOR, pS6, Rictor), and several metabolic enzymes (phosphofructokinase, lactate dehydrogenase-A, β-F1-ATPase, glucose-6-phosphate dehydrogenase, glutaminase). RICTOR amplification, as a potential mechanism of Rictor overexpression, was analyzed by FISH and digital droplet PCR. In total, 64% of the studied primary samples showed mTOR activity with an mTORC2 dominance (82%). Chemotherapy did not cause any relevant change in mTOR activity. Elevated mTOR activity was associated with a worse prognosis in relapsed cases. RICTOR amplification was not confirmed in any of the cases. Our findings suggest the importance of the Warburg effect and the pentose-phosphate pathway beside a glutamine demand in RMS cells. The expression pattern of the studied mTOR markers can explain the inefficacy of mTORC1 inhibitor therapy. Therefore, we suggest performing a detailed investigation of the mTOR profile before administering mTORC1 inhibitor therapy. Furthermore, our findings highlight that targeting the metabolic plasticity could be an alternative therapeutic approach.
Insights
mTORC2 pathway activation is common in rhabdomyosarcoma (RMS), impacting patient survival. Targeting metabolic pathways, not just mTORC1, may offer new therapeutic strategies for RMS.
Area of Science:
- Oncology
- Molecular Biology
- Metabolic Pathways
Background:
- Mammalian target of rapamycin (mTOR) activation is present in rhabdomyosarcoma (RMS), but mTOR complex 1 (mTORC1) inhibition has shown limited efficacy.
- mTOR activation influences metabolic pathways crucial for cancer cell survival and metastasis, which require further investigation in RMS.
- Understanding the specific mTOR complex activity and associated metabolic alterations is critical for developing effective RMS therapies.
Purpose of the Study:
- To analyze the expression of mTOR complexes (mTORC1 and mTORC2) and key metabolic enzymes in RMS tissues.
- To investigate the correlation between mTOR activity, metabolic enzyme expression, and patient prognosis in RMS.
- To evaluate the potential role of RICTOR amplification in mTORC2 overexpression and its clinical relevance.
Main Methods:
- Immunohistochemistry was performed on 65 primary RMS samples to assess the expression of mTOR pathway components (pmTOR, pS6, Rictor) and metabolic enzymes.
- Fluorescence in situ hybridization (FISH) and digital droplet PCR were used to detect RICTOR amplification.
- Statistical analysis was conducted to correlate marker expression with clinical outcomes and treatment response.
Main Results:
- 64% of RMS samples exhibited mTOR activity, with a notable dominance of mTORC2 signaling (82%).
- Elevated mTOR activity was associated with a worse prognosis in relapsed RMS cases; chemotherapy did not significantly alter mTOR activity.
- RICTOR amplification was not detected, suggesting other mechanisms for Rictor overexpression. The Warburg effect, pentose-phosphate pathway, and glutamine metabolism are highlighted as important in RMS.
Conclusions:
- The prevalence of mTORC2 activity and specific metabolic pathway alterations (Warburg effect, pentose-phosphate pathway, glutaminolysis) in RMS may explain the limited success of mTORC1 inhibitors.
- A detailed assessment of the mTOR signaling profile is recommended before initiating mTORC1 inhibitor therapy in RMS patients.
- Targeting metabolic plasticity represents a promising alternative therapeutic strategy for rhabdomyosarcoma.
More Related Videos
06:51Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer
Published on: July 21, 2018
07:38Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants
Published on: June 6, 2025
Related Concept Videos
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...
01:22PI3K/mTOR/AKT Signaling Pathway