Primary Aldosteronism: Spatial Multiomics Mapping of Genotype-Dependent Heterogeneity and Tumor Expansion of Aldosterone-Producing Adenomas

Siyuan Gong; Na Sun; Lucie S Meyer; Martina Tetti; Christina Koupourtidou; Stefan Krebs; Giacomo Masserdotti; Helmut Blum; William E Rainey; Martin Reincke; Axel Walch; Tracy Ann Williams

doi:10.1161/HYPERTENSIONAHA.123.20921

Primary Aldosteronism: Spatial Multiomics Mapping of Genotype-Dependent Heterogeneity and Tumor Expansion of Aldosterone-Producing Adenomas

Hypertension. 2023 Jul;80(7):1555-1567. doi: 10.1161/HYPERTENSIONAHA.123.20921. Epub 2023 May 1.

Authors

Siyuan Gong¹, Na Sun^#², Lucie S Meyer^#¹, Martina Tetti¹, Christina Koupourtidou^{3

4}, Stefan Krebs⁵, Giacomo Masserdotti^{6

7}, Helmut Blum⁵, William E Rainey^{8

9}, Martin Reincke¹, Axel Walch², Tracy Ann Williams¹

Affiliations

¹ Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ludwig-Maximilians-Universität (LMU) München, Germany (S.G., L.S.M., M.T., M.R., T.A.W.).
² Research Unit Analytical Pathology, German Research Center for Environmental Health, Helmholtz Zentrum München, Germany (N.S., A.W.).
³ Department for Cell Biology and Anatomy, Biomedical Center, LMU, Planegg-Martinsried, Germany (C.K.).
⁴ Graduate School Systemic Neurosciences, LMU, Planegg-Martinsried, Germany (C.K.).
⁵ Laboratory for Functional Genome Analysis, Gene Center, LMU Munich, Germany (S.K., H.B.).
⁶ Institute of Stem Cell Research, Helmholtz Center Munich, Neuherberg, Germany (G.M.).
⁷ Physiological Genomics, Biomedical Center (BMC), LMU, Planegg-Martinsried, Germany (G.M.).
⁸ Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI (W.E.R.).
⁹ Division of Metabolism, Endocrine, and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI (W.E.R.).

^# Contributed equally.

PMID: 37125608
PMCID: PMC10330203 (available on 2024-07-01)
DOI: 10.1161/HYPERTENSIONAHA.123.20921

Abstract

Background: Primary aldosteronism is frequently caused by an adrenocortical aldosterone-producing adenoma (APA) carrying a somatic mutation that drives aldosterone overproduction. APAs with a mutation in KCNJ5 (APA-KCNJ5^MUT) are characterized by heterogeneous CYP11B2 (aldosterone synthase) expression, a particular cellular composition and larger tumor diameter than those with wild-type KCNJ5 (APA-KCNJ5^WT). We exploited these differences to decipher the roles of transcriptome and metabolome reprogramming in tumor pathogenesis.

Methods: Consecutive adrenal cryosections (7 APAs and 7 paired adjacent adrenal cortex) were analyzed by spatial transcriptomics (10x Genomics platform) and metabolomics (in situ matrix-assisted laser desorption/ionization mass spectrometry imaging) co-integrated with CYP11B2 immunohistochemistry.

Results: We identified intratumoral transcriptional heterogeneity that delineated functionally distinct biological pathways. Common transcriptomic signatures were established across all APA specimens which encompassed 2 distinct transcriptional profiles in CYP11B2-immunopositive regions (CYP11B2-type 1 or 2). The CYP11B2-type 1 signature was characterized by zona glomerulosa gene markers and was detected in both APA-KCNJ5^MUT and APA-KCNJ5^WT. The CYP11B2-type 2 signature displayed markers of the zona fasciculata or reticularis and predominated in APA-KCNJ5^MUT. Metabolites that promote oxidative stress and cell death accumulated in APA-KCNJ5^WT. In contrast, antioxidant metabolites were abundant in APA-KCNJ5^MUT. Finally, APA-like cell subpopulations-negative for CYP11B2 gene expression-were identified in adrenocortical tissue adjacent to APAs suggesting the existence of tumor precursor states.

Conclusions: Our findings provide insight into intra- and intertumoral transcriptional heterogeneity and support a role for prooxidant versus antioxidant systems in APA pathogenesis highlighting genotype-dependent capacities for tumor expansion.

Keywords: adrenal glands; hyperaldosteronism; oxidative stress; spatial metabolomics; spatial transcriptomics.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adenoma* / metabolism
Adrenal Cortex Neoplasms* / complications
Adrenal Cortex Neoplasms* / genetics
Adrenocortical Adenoma* / metabolism
Aldosterone / metabolism
Antioxidants
Cytochrome P-450 CYP11B2 / genetics
Cytochrome P-450 CYP11B2 / metabolism
G Protein-Coupled Inwardly-Rectifying Potassium Channels / genetics
G Protein-Coupled Inwardly-Rectifying Potassium Channels / metabolism
Genotype
Humans
Hyperaldosteronism* / metabolism
Multiomics
Mutation

Substances

Aldosterone
Cytochrome P-450 CYP11B2
Antioxidants
G Protein-Coupled Inwardly-Rectifying Potassium Channels
KCNJ5 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding