Integrated Transcriptomics Reveals Evolutionary Trajectories and Cell Density‐Dependent Mechanisms in Aldosterone‐Producing Adenomas

Abstract 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.