Multiomics analysis unveils the cellular ecosystem with clinical relevance in aldosterone-producing adenomas with <i>KCNJ5</i> mutations
Abstract
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 KCNJ5 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 KCNJ5 mutations, providing insights into tumor biology that could inform future clinical approaches.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (20)
Maki Yokomoto-Umakoshi
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University
Masamichi Fujita
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University
Hironobu Umakoshi
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University
Tatsuki Ogasawara
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University
Norifusa Iwahashi
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University
Kohta Nakatani
Division of Metabolomics, Medical Research Center for High Depth Omics, Medical Institute of Bioregulation, Kyushu University
Hiroki Kaneko
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University
Tazuru Fukumoto
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University
Hiroshi Nakao
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University
Shojiro Haji
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University
Namiko Kawamura
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University
Shuichi Shimma
Department of Biotechnology, Graduate School of Engineering, Osaka University
Masahide Seki
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo
Yutaka Suzuki
Yoshihiro Izumi
Division of Metabolomics, Medical Research Center for High Depth Omics, Medical Institute of Bioregulation, Kyushu University
Yoshinao Oda
Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University
Masatoshi Eto
Department of Urology, Graduate School of Medical Sciences, Kyushu University
Seishi Ogawa
Takeshi Bamba
Yoshihiro Ogawa
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University