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Cardiovascular Endocrinology

SAT-277 - Multiomics analysis unveils the cellular ecosystem with clinical relevance in aldosterone-producing adenomas with KCNJ5 mutations

Saturday, June 13, 2026
9:30 AM - 4:30 PM CT
Disclosure(s):
Masamichi Fujita, MD, PhD: No financial relationships to disclose


Background:
Aldosterone-producing adrenal adenoma (APA) is a major subtype of primary aldosteronism, causing hypertension and cardiovascular disease through autonomous aldosterone secretion. APA is also associated with metabolic disorders such as diabetes mellitus and osteoporosis. Although APA may produce multiple steroid hormones including cortisol, the mechanisms underlying this steroidogenic diversity and its clinical impact remain unclear.

Objective:
To elucidate the cellular heterogeneity of steroidogenesis in APA and its regulatory mechanisms using multi-omics approaches, and to clarify its association with vertebral fractures (VFs).

Methods:
We performed single-cell RNA sequencing (n=8) and spatial transcriptomics (n=4) on APA tissues with KCNJ5 somatic mutations. Plasma steroid profiling using LC-MS/MS (28 steroids) and thoracolumbar radiography for VF assessment were conducted in patients with APA (n=27) and nonfunctioning adrenal tumors (NFATs; n=47).

Results:
Single-cell RNA sequencing revealed marked cellular heterogeneity in APA, identifying distinct aldosterone-producing and cortisol-producing tumor cell populations. Trajectory analysis identified two differentiation pathways: from stress-responsive cells to aldosterone-producing cells, and from stress-responsive cells to proliferative stromal-like cells via cortisol-producing cells. These cell populations showed spatial segregation. Tumor microenvironment analysis showed that lipid-associated macrophages strongly interacted with cortisol-producing and stromal-like cells, with macrophage abundance correlating with plasma cortisol levels and tumor size. Clinically, VFs were more frequent in APA than in NFATs (40.7% vs 14.9%). Plasma steroid profiling distinguished patients with and without VFs, with cortisol showing the strongest contribution. Plasma cortisol levels were significantly higher in patients with VFs. Imaging mass spectrometry confirmed intratumoral cortisol production, which positively correlated with circulating cortisol levels.

Conclusions:
Multi-omics analysis revealed that APA harbors a complex cellular ecosystem characterized by steroidogenic plasticity, spatial heterogeneity, and tumor–microenvironment interactions, potentially contributing to the development of vertebral fractures.

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