The adrenal cortex, the external part of the adrenal glands, is divided into three distinct anatomical and functional zones, each specialized in the production of specific steroid hormones. From the periphery to the center, the zona glomerulosa (ZG) secretes aldosterone, the zona fasciculata (ZF) cortisol, and the zona reticularis (ZR) androgens.
Tumors of the adrenal cortex include benign tumors, the most common of which are adenomas, and very rare malignant tumors called adrenocortical carcinomas (AC). These pathologies are associated with high morbidity, linked either to hormonal hypersecretion for all tumor types, or to tumor growth and metastatic potential for AC.
Therapeutic options for advanced AC are limited, with response rates to conventional treatments (mitotane, platinum salts, or immune checkpoint inhibitors) not exceeding 25%.
In this study, Jérôme Bertherat's team, in partnership with the CYBIO, HISTIM, and GENOM'IC platforms at the Institut Cochin, provides an atlas at the individual cell level of the normal adrenal cortex and different types of adrenal cortex tumors.
The team analyzed 170,000 cells from four normal adrenal glands and 34 adrenal cortex tumors (20 SCs and 14 benign tumors) using single-nucleus RNA sequencing (10x Genomics). The resulting signatures were validated in situ using spatial transcriptomics (10x Genomics) and immunohistochemistry. The contributions of each cell were accurately localized using bulk transcriptome deconvolution in public data from over 200 ACs.
In the normal adrenal gland, this study identifies a novel cell population intermediate between the GZ and FZ cells. This transition state supports the hypothesis of GZ to FZ trans-differentiation in the zonation of the adrenal cortex in humans.
Although the microenvironment of adrenal tumors is relatively poor, it contains different immune and stromal populations that preferentially associate with certain steroid cell types to form tumor ecotypes.
One ecotype combines cancer-associated fibroblasts and tumor endothelial cells, with signatures of hypoxia and mitosis in the steroid cells. Another ecotype combines exhausted T cells with a fasciculated signature in the steroid cells. This ecotype may reflect the adverse impact of local secretion of cortisol, a hormone known for its immunosuppressive effects, on the immune microenvironment. These ecotypes are associated with a poor prognosis.
Conversely, a third ecotype combines inflammatory macrophages with a reticulated signature in steroid cells and is associated with a much better prognosis. This ecotype may reflect a more favorable impact of local androgen secretion on the immune microenvironment.
This single-cell atlas could impact the therapeutic strategy in AC.
The tumor ecotypes described in this study reflect specific interactions between steroid tumor cells and their microenvironment, potentially constituting new therapeutic targets. In particular, the impact of steroid differentiation of tumor cells on the immune microenvironment opens the prospect of modulating the cortisol/androgen balance to improve the response to immune checkpoint inhibitors.
Reference
Jouinot A, Martin Y, Violon F, Foulonneau T, Bendjelal Y, Calvet P, Izac B, Letourneur F, Bertholle C, Andrieu M, Onifarasoaniaina R, Favier M, de Guitaut C, Fraikin A, de Murat D, Armignacco R, Benanteur N, Birtolo MF, Sibony M, Perlemoine K, Vaduva P, Bouys L, Bonnet-Serrano F, Dousset B, Gaillard M, Pasmant E, Barat M, Dohan A, Haissaguerre M, Tabarin A, Libé R, Guignat L, Groussin L, Berthon A, Ragazzon B, Bertherat J, Assié G. Impact of steroid differentiation on tumor microenvironment revealed by single-nucleus atlas of adrenal tumors. Nat Commun. 2025 Oct 6;16(1):8860. doi: 10.1038/s41467-025-63912-2. PMID: 41053133.
