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Updated: Jun 28, 2025
Tumorsphere Derivation and Treatment from Primary Tumor Cells Isolated from Mouse Rhabdomyosarcomas
Published on: September 13, 2019
Differential metabolic secretion between muscular dystrophy mouse-derived spindle cell sarcomas and rhabdomyosarcomas
Emma Tabe Eko Niba1,2, Hiroyuki Awano3, Noriyuki Nishimura4
1Laboratory of Molecular and Biochemical Research, Biomedical Research Core Facilities, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Abstract:
The dystrophin gene (Dmd) is recognized for its significance in Duchenne muscular dystrophy (DMD), a lethal and progressive skeletal muscle disease. Some patients with DMD and model mice with muscular dystrophy (mdx) spontaneously develop various types of tumors, among which rhabdomyosarcoma (RMS) is the most prominent. By contrast, spindle cell sarcoma (SCS) has rarely been reported in patients or mdx mice. In this study, we aimed to use metabolomics to better understand the rarity of SCS development in mdx mice. Gas chromatography-mass spectrometry was used to compare the metabolic profiles of spontaneously developed SCS and RMS tumors from mdx mice, and metabolite supplementation assays and silencing experiments were used to assess the effects of metabolic differences in SCS tumor-derived cells. The levels of 75 metabolites exhibited differences between RMS and SCS, 25 of which were significantly altered. Further characterization revealed downregulation of nonessential amino acids, including alanine, in SCS tumors. Alanine supplementation enhanced the growth, epithelial mesenchymal transition, and invasion of SCS cells. Reduction of intracellular alanine via knockdown of the alanine transporter Slc1a5 reduced the growth of SCS cells. Lower metabolite secretion and reduced proliferation of SCS tumors may explain the lower detection rate of SCS in mdx mice. Targeting of alanine depletion pathways may have potential as a novel treatment strategy.NEW & NOTEWORTHY To the best of our knowledge, SCS has rarely been identified in patients with DMD or mdx mice. We observed that RMS and SCS tumors that spontaneously developed from mdx mice with the same Dmd genetic background exhibited differences in metabolic secretion. We proposed that, in addition to dystrophin deficiency, the levels of secreted metabolites may play a role in the determination of tumor-type development in a Dmd-deficient background.
Insights
Spindle cell sarcoma (SCS) is rare in Duchenne muscular dystrophy (DMD) models. Metabolomic analysis revealed lower alanine levels in SCS tumors, and supplementing alanine enhanced SCS cell growth, suggesting a potential therapeutic target for this rare cancer.
Area of Science:
- Oncology
- Metabolomics
- Genetics
Background:
- Duchenne muscular dystrophy (DMD) is a severe skeletal muscle disease caused by dystrophin gene (Dmd) mutations.
- Spontaneously occurring tumors, including rhabdomyosarcoma (RMS), are observed in DMD patients and mdx mice.
- Spindle cell sarcoma (SCS) is a rare tumor type in the context of DMD and mdx mouse models.
Purpose of the Study:
- To investigate the metabolic differences between RMS and SCS tumors in mdx mice.
- To understand the metabolic factors contributing to the rarity of SCS development.
- To explore potential therapeutic strategies targeting metabolic pathways in SCS.
Main Methods:
- Comparative metabolomics using gas chromatography-mass spectrometry (GC-MS) on mdx mouse-derived RMS and SCS tumors.
- Metabolite supplementation assays and gene silencing experiments on SCS tumor-derived cells.
- Analysis of intracellular alanine levels and the role of the alanine transporter Slc1a5.
Main Results:
- Significant metabolic differences were observed between RMS and SCS tumors, with 25 out of 75 altered metabolites being significant.
- SCS tumors showed downregulation of nonessential amino acids, notably alanine.
- Alanine supplementation promoted SCS cell growth, epithelial-mesenchymal transition, and invasion, while Slc1a5 knockdown reduced growth.
Conclusions:
- Metabolic secretion profiles differ between RMS and SCS tumors in a Dmd-deficient background.
- Downregulation of alanine may contribute to the rarity and reduced proliferation of SCS.
- Targeting alanine depletion pathways presents a potential novel therapeutic strategy for SCS in DMD contexts.
