Single-nuclei and bulk-tissue gene-expression analysis of pheochromocytoma and paraganglioma links disease subtypes with tumor microenvironment

Magnus Zethoven, Luciano Martelotto, Andrew Pattison, Blake Bowen, Shiva Balachander, Aidan Flynn, Fernando J. Rossello, Annette Hogg, Julie A. Miller, Zdenek Frysak, Sean Grimmond, Lauren Fishbein, Arthur S. Tischler, Anthony J. Gill, Rodney J. Hicks, Patricia L.M. Dahia, Roderick Clifton-Bligh, Karel Pacak, Richard W. Tothill

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Pheochromocytomas (PC) and paragangliomas (PG) are rare neuroendocrine tumors associated with autonomic nerves. Here we use single-nuclei RNA-seq and bulk-tissue gene-expression data to characterize the cellular composition of PCPG and normal adrenal tissues, refine tumor gene-expression subtypes and make clinical and genotypic associations. We confirm seven PCPG gene-expression subtypes with significant genotype and clinical associations. Tumors with mutations in VHL, SDH-encoding genes (SDHx) or MAML3-fusions are characterized by hypoxia-inducible factor signaling and neoangiogenesis. PCPG have few infiltrating lymphocytes but abundant macrophages. While neoplastic cells transcriptionally resemble mature chromaffin cells, early chromaffin and neuroblast markers are also features of some PCPG subtypes. The gene-expression profile of metastatic SDHx-related PCPG indicates these tumors have elevated cellular proliferation and a lower number of non-neoplastic Schwann-cell-like cells, while GPR139 is a potential theranostic target. Our findings therefore clarify the diverse transcriptional programs and cellular composition of PCPG and identify biomarkers of potential clinical significance.

Original languageEnglish (US)
Article number6262
JournalNature communications
Volume13
Issue number1
DOIs
StatePublished - Dec 2022
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • General
  • Physics and Astronomy(all)

Fingerprint

Dive into the research topics of 'Single-nuclei and bulk-tissue gene-expression analysis of pheochromocytoma and paraganglioma links disease subtypes with tumor microenvironment'. Together they form a unique fingerprint.

Cite this