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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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter 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
Zeitschrift Hypertension
Quellenangaben Band: 80, Heft: 7, Seiten: 1555-1567 Artikelnummer: , Supplement: ,
Verlag Lippincott Williams & Wilkins
Verlagsort Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Analytical Pathology (AAP)
Institute of Stem Cell Research (ISF)
Förderungen 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