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 and Richard W. Tothill ()
Additional contact information
Magnus Zethoven: Peter MacCallum Cancer Centre
Luciano Martelotto: University of Melbourne
Andrew Pattison: University of Melbourne
Blake Bowen: University of Melbourne
Shiva Balachander: University of Melbourne
Aidan Flynn: University of Melbourne
Fernando J. Rossello: University of Melbourne
Annette Hogg: Peter MacCallum Cancer Centre
Julie A. Miller: Royal Melbourne Hospital
Zdenek Frysak: Palacky University Olomouc and University Hospital Olomouc
Sean Grimmond: University of Melbourne
Lauren Fishbein: University of Colorado
Arthur S. Tischler: Tufts Medical Centre
Anthony J. Gill: University of Sydney
Rodney J. Hicks: Peter MacCallum Cancer Centre
Patricia L. M. Dahia: University of Texas Health Science Center at San Antonio (UTHSCSA)
Roderick Clifton-Bligh: University of Sydney
Karel Pacak: Eunice Kennedy Shriver National Institute of Child Health and Human Development
Richard W. Tothill: University of Melbourne

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34011-3

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DOI: 10.1038/s41467-022-34011-3

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