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Gong, S.* ; Sun, N. ; Meyer, L.S.* ; Tetti, M.* ; Koupourtidou, C.* ; Krebs, S.* ; Masserdotti, G. ; Blum, H.* ; Rainey, W.E.* ; Reincke, M.* ; Walch, A.K. ; Williams, T.A.*

Primary aldosteronism: Spatial multi-omics mapping of genotype-dependent heterogeneity and tumor expansion of aldosterone-producing adenomas.

Hypertension 80, 1555-1567 (2023)
Postprint DOI PMC
Open Access Green
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-KCNJ5MUT) are characterized by heterogeneous CYP11B2 (aldosterone synthase) expression, a particular cellular composition and larger tumor diameter than those with wild-type KCNJ5 (APA-KCNJ5WT). 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-KCNJ5MUT and APA-KCNJ5WT. The CYP11B2-type 2 signature displayed markers of the zona fasciculata or reticularis and predominated in APA-KCNJ5MUT. Metabolites that promote oxidative stress and cell death accumulated in APA-KCNJ5WT. In contrast, antioxidant metabolites were abundant in APA-KCNJ5MUT. 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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Adrenal Glands ; Hyperaldosteronism ; Oxidative Stress ; Spatial Metabolomics ; Spatial Transcriptomics; Polyunsaturated Fatty-acids; Pentose-phosphate Pathway; K+ Channel Mutations; Somatic Mutations; Consensus; Growth; Peroxidation; Metabolism; Subtypes; Society
ISSN (print) / ISBN 0194-911x
e-ISSN 1524-4563
Journal Hypertension
Quellenangaben Volume: 80, Issue: 7, Pages: 1555-1567 Article Number: , Supplement: ,
Publisher Lippincott Williams & Wilkins
Publishing Place Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Research Unit Analytical Pathology (AAP)
Institute of Stem Cell Research (ISF)
Grants China Scholarship Council
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases
Else Kroener-Fresenius Stiftung
Deutsche Forschungsgemeinschaft (DFG)
European Research Council (ERC) under the European Union