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Integrated transcriptomics reveals evolutionary trajectories and cell density-dependent mechanisms in aldosterone-Producing adenomas.
Adv. Sci.:e05410 (2026)
Aldosterone-producing adenomas (APAs) and micronodules (APMs) are histopathological lesions that can cause a prevalent form of secondary hypertension called primary aldosteronism. Using integrated single-cell/nucleus and spatial transcriptomics, it demonstrates substantial heterogeneity between APMs and APAs, alongside an immunosuppressive tumor microenvironment in APAs. Pseudotime analyses reveal two distinct evolutionary trajectories in APAs: a direct progression from zona glomerulosa cells to APAs, observed specifically in KCNJ5-mutated tumors, and a stepwise path from zona glomerulosa cells to APMs and then to APAs, present in both KCNJ5-mutated APAs and APAs without KCNJ5 mutations. Within KCNJ5-mutated APAs, we identified two distinct cellular states with different differentiation potentials: a progenitor-like state (high differentiation potential) and a mature state (low differentiation potential). This uncovered a spectrum of molecular and functional shifts during APA progression involving pathways of oxidative stress (including mechanisms leading to cell death by ferroptosis) and focal adhesion (influenced by cell density). In vitro studies in human adrenal cells demonstrate that TAZ activation regulates ferroptosis sensitivity in response to cell density changes. The findings enhance understanding of the transcriptional diversity in APMs and APAs and elucidate complex molecular alterations underlying APA pathogenesis.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Aldosterone‐producing Adenomas ; Evolutionary Trajectory ; Single‐cell/nucleus Transcriptomics ; Spatial Transcriptomics ; Tumor Microenvironment; Somatic Mutations; Channel Mutations; Heterogeneity; Ferroptosis; Clusters; Macrophages; Prevalence; Diagnosis; Inference; Atp1a1
ISSN (print) / ISBN
2198-3844
e-ISSN
2198-3844
Journal
Advanced science
Quellenangaben
Article Number: e05410
Publisher
Wiley
Publishing Place
Weinheim
Reviewing status
Peer reviewed
Grants
Projekt DEAL
European Research Council under the European Union's Horizon 2020 research and innovation program
Else Kroener-Fresenius Stiftung
Else Kroener Hyperaldosteronismus-German Conn Registry
China Scholarship Council-Deutscher Akademischer Austauschdienst (CSC-DAAD) post-doctoral fellowship
National Natural Science Foundation of China
China Postdoctoral Science Foundation
China Scholarship Council
Deutsche Forschungsgemeinschaft (DFG)
European Research Council under the European Union's Horizon 2020 research and innovation program
Else Kroener-Fresenius Stiftung
Else Kroener Hyperaldosteronismus-German Conn Registry
China Scholarship Council-Deutscher Akademischer Austauschdienst (CSC-DAAD) post-doctoral fellowship
National Natural Science Foundation of China
China Postdoctoral Science Foundation
China Scholarship Council
Deutsche Forschungsgemeinschaft (DFG)