Multiomics analysis unveils the cellular ecosystem with clinical relevance in aldosterone-producing adenomas with <i>KCNJ5</i> mutations
Aldosterone-producing adenomas (APA), a major endocrine tumor and leading subtype of primary aldosteronism, cause secondary hypertension with high cardiometabolic risks. Despite potentially producing multiple steroid hormones, detailed cellular mechanisms in APA remain insufficiently studied. Our multiomics analysis focusing on APA with <i>KCNJ5</i> mutations, which represent the most common genetic form, revealed marked cellular heterogeneity. Tumor cell reprogramming initiated from stress-responsive cells to aldosterone-producing or cortisol-producing cells, with the latter progressing to proliferative stromal-like cells. These cell subtypes showed spatial segregation, and APA exhibited genomic intratumor heterogeneity. Among the nonparenchymal cells, lipid-associated macrophages, which were abundant in APA, might promote the progression of cortisol-producing and stromal-like cells, suggesting their role in the tumor microenvironment. Intratumor cortisol synthesis was correlated with increased blood cortisol levels, which were associated with the development of vertebral fractures, a hallmark of osteoporosis. This study unveils the complex cellular ecosystem with clinical relevance in APA with <i>KCNJ5</i> mutations, providing insights into tumor biology that could inform future clinical approaches.
Authors
- Masatoshi Eto (ORCID: https://orcid.org/0000-0002-3312-9930)
- Shuichi Shimma (ORCID: https://orcid.org/0000-0002-4699-6590)
- Hironobu Umakoshi (ORCID: https://orcid.org/0000-0003-4293-287X)
- Kohta Nakatani (ORCID: https://orcid.org/0000-0002-8270-6829)
- Seishi Ogawa (ORCID: https://orcid.org/0000-0002-7778-5374)
- Masahide Seki (ORCID: https://orcid.org/0000-0001-6091-8698)
- Yoshinao Oda (ORCID: https://orcid.org/0000-0001-9636-1182)
- Tatsuki Ogasawara (ORCID: https://orcid.org/0000-0003-4766-7817)
- Shojiro Haji (ORCID: https://orcid.org/0000-0003-3651-2836)
- Yutaka Suzuki (ORCID: https://orcid.org/0000-0003-4852-1879)
- Norifusa Iwahashi (ORCID: https://orcid.org/0000-0001-9881-9126)
- Hiroki Kaneko (ORCID: https://orcid.org/0000-0001-6998-1917)
- Maki Yokomoto‐Umakoshi (ORCID: https://orcid.org/0000-0003-0934-9148)
- Masamichi Fujita (ORCID: https://orcid.org/0009-0008-1316-1774)
- Yoshihiro Ogawa (ORCID: https://orcid.org/0000-0002-0834-2836)
- Namiko Kawamura (ORCID: https://orcid.org/0000-0002-9206-2844)
- Takeshi Bamba (ORCID: https://orcid.org/0000-0002-7442-2738)
- Hiroshi Nakao
- Yoshihiro Izumi (ORCID: https://orcid.org/0000-0003-4608-4652)
- Tazuru Fukumoto (ORCID: https://orcid.org/0009-0003-2870-2776)
Institutions
- Kyushu University (JP)
- Kyoto University (JP)
- The University of Tokyo (JP)
- The University of Osaka (JP)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2025-02-26
- DOI
- https://doi.org/10.1073/pnas.2421489122
- Citations
- 9
- Primary Topic
- Hormonal Regulation and Hypertension
- Type
- article
- Field-Weighted Citation Impact
- 11.65
Funders
- Takeda Science Foundation
- Japan Foundation for Applied Enzymology
- Nakatomi Foundation
- Uehara Memorial Foundation
- Japan Agency for Medical Research and Development
- Ministry of Education, Culture, Sports, Science and Technology
- Research Promotion Foundation
- Secom Science and Technology Foundation
- Hokkaido University
- Ono Medical Research Foundation
- Japan Society for the Promotion of Science
- Moonshot Research and Development Program