Journal Article

Impact of steroid differentiation on tumor microenvironment revealed by single-nucleus atlas of adrenal tumors

Ragazzon, Bruno, Bendjelal, Yanis, Foulonneau, Thomas, Pasmant, Eric, Martin, Yoann, Benanteur, Nesrine, Bouys, Lucas, Bonnet-Serrano, Fidéline, Fraikin, Archibald, Libé, Rossella, Jouinot, Anne, Berthon, Annabel, Armignacco, Roberta, Birtolo, Maria Francesca, Tabarin, Antoine, Andrieu, Muriel, Vaduva, Patricia, Dohan, Anthony, Gaillard, Martin, Sibony, Mathilde, Barat, Maxime, Groussin, Lionel, Onifarasoaniaina, Rachel, Haissaguerre, Magalie, Bertherat, Jérôme, de Guitaut, Charlène, Violon, Florian, Izac, Brigitte, Favier, Maryline, de Murat, Daniel, Perlemoine, Karine, Assié, Guillaume, Guignat, Laurence, Letourneur, Franck, Dousset, Bertrand, Bertholle, Céline, Calvet, Philip

2025

Overview

Adrenocortical carcinomas (ACC) are aggressive and resistant to medical treatment. This study reports a single-nucleus transcriptome atlas of steroid and microenvironment cells in 38 human normal adrenals and adrenocortical tumors. We identify intermediate-state cells between glomerulosa and fasciculata, a transition state in the centripetal trans-differentiation of normal steroid cells. In tumors, steroid cells show expression programs reflecting this zonation. Although ACC microenvironment is scarce, its signatures combine with those of steroid cells into ecotypes. A first ecotype combines cancer-associated fibroblasts, tumor-associated endothelial cells, with hypoxia and mitosis signatures in steroid cells. Another ecotype combines exhausted T cells, with fasciculata steroid signature. These ecotypes are associated with poor survival. Conversely, a third ecotype combines inflammatory macrophages, with reticularis steroid signature, and better outcome. These steroid/microenvironment cells interplays improve outcome predictions and may open therapeutic options in aggressive ACC, through immune microenvironment activation by modulating glucocorticoids/androgens balance. Adrenocortical carcinomas (ACC) are aggressive and often resistant to therapy. Here, the authors provide a single-nucleus transcriptomic atlas of ACCs and normal adrenal glands, finding ecotypes in steroid and microenvironment cells that are associated with clinical outcomes.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 49/39 / 49/91 / 631/67/2329 / 631/67/327 / 692/4028/67/1459/1280 / 692/4028/67/69 / 82/51 / Adrenal Cortex Neoplasms - genetics / Adrenal Cortex Neoplasms - metabolism / Adrenal Cortex Neoplasms - pathology / Adrenal glands / Adrenal Glands - metabolism / Adrenal Glands - pathology / Adrenocortical Carcinoma - genetics / Adrenocortical Carcinoma - metabolism / Adrenocortical Carcinoma - pathology / Androgens / Annotations / Approximation / Cancer / Cancer-Associated Fibroblasts - metabolism / Cancer-Associated Fibroblasts - pathology / Carcinoma / Cell adhesion & migration / Cell Differentiation / Cell division / Cell Nucleus - genetics / Cell Nucleus - metabolism / Differentiation / Ecotypes / Endothelial cells / Female / Gene expression / Gene Expression Regulation, Neoplastic / Glucocorticoids / Heat shock proteins / Humanities and Social Sciences / Humans / Hyperplasia / Hypoxia / Immunohistochemistry / Life Sciences / Lymphocytes / Lymphocytes T / Macrophages / Male / Medical treatment / Mitosis / multidisciplinary / Quantitative Methods / Science / Science (multidisciplinary) / Signatures / Single-Cell Analysis / Steroids / Steroids - metabolism / Transcriptome / Transcriptomes / Transcriptomics / Tumor microenvironment / Tumor Microenvironment - genetics / Tumors / Zonation