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A xenograft and cell line model of SDH-deficient pheochromocytoma derived from Sdhb+/- rats
James F Powers1, Brent Cochran2, James D Baleja2
1Department of Pathology and Laboratory Medicine, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts, USA.
Abstract:
Tumors caused by loss-of-function mutations in genes encoding TCA cycle enzymes have been recently discovered and are now of great interest. Mutations in succinate dehydrogenase (SDH) subunits cause pheochromocytoma/paraganglioma (PCPG) and syndromically associated tumors, which differ phenotypically and clinically from more common SDH-intact tumors of the same types. Consequences of SDH deficiency include rewired metabolism, pseudohypoxic signaling and altered redox balance. PCPG with SDHB mutations are particularly aggressive, and development of treatments has been hampered by lack of valid experimental models. Attempts to develop mouse models have been unsuccessful. Using a new strategy, we developed a xenograft and cell line model of SDH-deficient pheochromocytoma from rats with a heterozygous germline Sdhb mutation. The genome, transcriptome and metabolome of this model, called RS0, closely resemble those of SDHB-mutated human PCPGs, making it the most valid model now available. Strategies employed to develop RS0 may be broadly applicable to other SDH-deficient tumors.
Insights
Researchers developed a novel rat model, RS0, for studying SDH-deficient pheochromocytoma (PCPG). This model closely mimics human SDHB-mutated PCPG, offering a valuable tool for understanding and treating these aggressive tumors.
Area of Science:
- Oncology
- Metabolic Engineering
- Genetics
Background:
- Loss-of-function mutations in TCA cycle enzymes are linked to specific tumor types.
- Succinate dehydrogenase (SDH) mutations cause pheochromocytoma/paraganglioma (PCPG) with distinct clinical features.
- SDH deficiency leads to metabolic rewiring, pseudohypoxic signaling, and altered redox balance.
Purpose of the Study:
- To develop a valid experimental model for SDH-deficient pheochromocytoma (PCPG).
- To overcome limitations of previous attempts, particularly the failure of mouse models.
- To provide a resource for investigating aggressive SDHB-mutated PCPG.
Main Methods:
- Development of a rat xenograft and cell line model (RS0) from rats with a germline Sdhb mutation.
- Comprehensive analysis of the model's genome, transcriptome, and metabolome.
- Comparison of the model's molecular profile with human SDHB-mutated PCPGs.
Main Results:
- The RS0 model accurately reflects the genomic, transcriptomic, and metabolomic profiles of human SDHB-mutated PCPGs.
- This xenograft and cell line model represents the most valid available resource for SDH-deficient PCPG research.
- The methodology used may be applicable to other SDH-deficient tumor types.
Conclusions:
- The RS0 rat model is a highly accurate and valuable tool for studying SDH-deficient pheochromocytoma.
- This model facilitates research into the aggressive nature of SDHB-mutated PCPG.
- The developed strategy holds potential for creating models of other SDH-deficient tumors.
