Developmental insights into PPGL syndromes

FARE Award Winner

Authors

• Y Cole
• J Rosenblum
• H Wang
• I Indig
• T D
• J Munasignhe
• D Donahue
• A Sowalsky
• S Trostel
• K Pacak
• Z Zhuang

Abstract

Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors derived from the neural crest (NC) that can present as early as the first decade of life. Genetic variants in genes such as the succinate dehydrogenase complex subunits (SDHx) and hypoxia-inducible factor 2-alpha (HIF2A) can lead to the activation of hypoxia-inducible pathways, leading to vasculogenesis and tumorigenesis. We previously discovered a sporadic neoplastic syndrome characterized by paraganglioma and developmental malformations due to mosaic gain-of-function variants in mosaic HIF2A mutations. We believe the dysregulated response to oxygen tension in developing NC, such as through pseudohypoxia signaling driven by genetic variants, leads to the co-occurrence of developmental malformations and tumors. To better understand the implications of SDHB variants on NC and PPGL development, we evaluated a transgenic “two hit” SDHB mouse model, that we developed to recapitulate the associated human PPGL syndrome, using high-resolution ex vivo imaging and subsequent immunohistochemistry (IHC) and ddPCR of affected tissues. These studies demonstrated the adrenal glands had features suggesting abnormal development such as significantly enlarged adrenal medullas and abnormal intra-adrenal features including medullary tails and vascular defects compared to wild-type (WT) adrenals. We observed islands of medullary cells with a poorly demarcated border between the medulla and cortex, using histology and IHC, suggesting improper development. To fully understand the role of sdhb in developmental processes in the neural crest, we are extending our studies to include both embryos and early postnatal timepoints. These results suggest a role of Sdhb in adrenal embryonic and PPGL development.

Scientific Focus Area: Cancer Biology

This page was last updated on Monday, September 25, 2023