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

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). Here, we used spatial transcriptomics profiling of adrenal tissue cryosections to define the role of transcriptomic reprogramming in APA pathophysiology. Our findings advance the understanding of the transcriptional context of inter- and intra-tumoral APA heterogeneity and provide novel insight into the genotype-dependent tumor expansion capabilities of APAs. Consecutive adrenal cryosections (7 APAs and 7 paired adjacent adrenal cortex) were analyzed by spatial transcriptomics (10x Genomics platform) with CYP11B2 immunohistochemistry. To delineate and compare APA intra-tumoral transcriptional heterogeneity stratified by genotype, we conducted spatial transcriptomics of adrenal cryosections from APA-KCNJ5MUT(n= 4) and APA-KCNJ5WT(n= 3)