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American Heart Association, Hypertension, 7(80), p. 1555-1567, 2023

DOI: 10.1161/hypertensionaha.123.20921

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

This paper was not found in any repository, but could be made available legally by the author.
This paper was not found in any repository, but could be made available legally by the author.

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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.