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

Author

Listed:
  • 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
    Epworth 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
    Royal North Shore Hospital
    Royal North Shore Hospital)

  • 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
    Royal North Shore Hospital)

  • Karel Pacak

    (Eunice Kennedy Shriver National Institute of Child Health and Human Development)

  • Richard W. Tothill

    (University of Melbourne
    University of Melbourne)

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.

Suggested Citation

  • 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 , 2022. "Single-nuclei and bulk-tissue gene-expression analysis of pheochromocytoma and paraganglioma links disease subtypes with tumor microenvironment," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34011-3
    DOI: 10.1038/s41467-022-34011-3
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    References listed on IDEAS

    as
    1. Xiaodong Liu & John F. Ouyang & Fernando J. Rossello & Jia Ping Tan & Kathryn C. Davidson & Daniela S. Valdes & Jan Schröder & Yu B. Y. Sun & Joseph Chen & Anja S. Knaupp & Guizhi Sun & Hun S. Chy & Z, 2020. "Reprogramming roadmap reveals route to human induced trophoblast stem cells," Nature, Nature, vol. 586(7827), pages 101-107, October.
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    3. Rui Hou & Elena Denisenko & Huan Ting Ong & Jordan A. Ramilowski & Alistair R. R. Forrest, 2020. "Predicting cell-to-cell communication networks using NATMI," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
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    Cited by:

    1. Bruna Calsina & Elena Piñeiro-Yáñez & Ángel M. Martínez-Montes & Eduardo Caleiras & Ángel Fernández-Sanromán & María Monteagudo & Rafael Torres-Pérez & Coral Fustero-Torre & Marta Pulgarín-Alfaro & Ed, 2023. "Genomic and immune landscape Of metastatic pheochromocytoma and paraganglioma," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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