Primary Aldosteronism: Metabolic Reprogramming and the Pathogenesis of Aldosterone-Producing Adenomas

Simple Summary Primary aldosteronism is a common form of endocrine hypertension often caused by a hyper-secreting tumor of the adrenal cortex called an aldosterone-producing adenoma. Metabolic reprogramming plays a role in tumor progression and influences the tumor immune microenvironment by limiting immune-cell infiltration and suppressing its anti-tumor function. We hypothesized that the development of aldosterone-producing adenomas involves metabolic adaptations of its component tumor cells and intrinsically influences tumor pathogenesis. Herein, we use state-of-the-art computational tools for the comprehensive analysis of array-based gene expression profiles to demonstrate metabolic reprogramming and remodeling of the immune microenvironment in aldosterone-producing adenomas compared with paired adjacent adrenal cortical tissue. Our findings suggest metabolic alterations may function in the pathogenesis of aldosterone-producing adenomas by conferring survival advantages to their component tumor cells. Aldosterone-producing adenomas (APAs) are characterized by aldosterone hypersecretion and deregulated adrenocortical cell growth. Increased energy consumption required to maintain cellular tumorigenic properties triggers metabolic alterations that shape the tumor microenvironment to acquire necessary nutrients, yet our knowledge of this adaptation in APAs is limited. Here, we investigated adrenocortical cell-intrinsic metabolism and the tumor immune microenvironment of APAs and their potential roles in mediating aldosterone production and growth of adrenocortical cells. Using multiple advanced bioinformatics methods, we analyzed gene expression datasets to generate distinct metabolic and immune cell profiles of APAs versus paired adjacent cortex. APAs displayed activation of lipid metabolism, especially fatty acid beta-oxidation regulated by PPAR alpha, and glycolysis. We identified an immunosuppressive microenvironment in APAs, with reduced infiltration of CD45(+) immune cells compared with adjacent cortex, validated by CD45 immunohistochemistry (3.45-fold, p < 0.001). APAs also displayed an association of lipid metabolism with ferroptosis and upregulation of antioxidant systems. In conclusion, APAs exhibit metabolic reprogramming towards fatty acid beta-oxidation and glycolysis. Increased lipid metabolism via PPAR alpha may serve as a key mechanism to modulate lipid peroxidation, a hallmark of regulated cell death by ferroptosis. These findings highlight survival advantages for APA tumor cells with metabolic reprogramming properties.

Automated summary

Primary aldosteronism, caused by hyper-secreting tumor of the adrenal cortex, involves metabolic adaptations of tumor cells, shaping the tumor microenvironment for survival advantages. Metabolic reprogramming towards fatty acid beta-oxidation and glycolysis, along with an immunosuppressive microenvironment, play crucial roles in aldosterone-producing adenomas' pathogenesis.