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.
Highlights
Paraganglia are neuroendocrine structures that develop from neural crest progenitors associated with paraxial sympathetic nerves and from parasympathetic nerves in the head and neck
Liver tissue from heterozygous rats carrying each of the three germline Sdhb deletions showed approximately 50% reduced expression of Sdhb mRNA and enzyme activity compared to age-matched WT rats and 68% of normal protein expression based on densitometry data
The biological significance of haploinsufficiency was confirmed by crossing Sdhb+/- X Sdhb+/- rats to generate homozygotes, which resulted in embryos developmentally stalled at ~5–6 days, as reported for Sdhb-/- mice (Piruat et al 2004)
Summary
Paraganglia are neuroendocrine structures that develop from neural crest progenitors associated with paraxial sympathetic nerves and from parasympathetic nerves in the head and neck. The major sympathetic paraganglion is the adrenal medulla. Tumors called paragangliomas can arise anywhere in the distribution of normal paraganglia. By definition an intra-adrenal paraganglioma (PG) is called a pheochromocytoma (PC) (Lloyd et al 2017). At least 40% of pheochromocytomas and paragangliomas (PCPGs) are hereditary, and germline mutations of at least 17 functionally diverse genes can lead to their development (Dahia 2017). Mutations of genes encoding subunits of succinate dehydrogenase (SDH) account for the largest number of familial aggregates of these tumors and for more than 20–30% of the tumors that metastasize
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
