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

Anne Jouinot (), Yoann Martin, Florian Violon, Thomas Foulonneau, Yanis Bendjelal, Philip Calvet, Brigitte Izac, Franck Letourneur, Céline Bertholle, Muriel Andrieu, Rachel Onifarasoaniaina, Maryline Favier, Charlène Guitaut, Archibald Fraikin, Daniel Murat, Roberta Armignacco, Nesrine Benanteur, Maria Francesca Birtolo, Mathilde Sibony, Karine Perlemoine, Patricia Vaduva, Lucas Bouys, Fidéline Bonnet-Serrano, Bertrand Dousset, Martin Gaillard, Eric Pasmant, Maxime Barat, Anthony Dohan, Magalie Haissaguerre, Antoine Tabarin, Rossella Libé, Laurence Guignat, Lionel Groussin, Annabel Berthon, Bruno Ragazzon, Jérôme Bertherat and Guillaume Assié ()
Additional contact information
Anne Jouinot: Université Paris Cité, CNRS, Inserm, Institut Cochin
Yoann Martin: Université Paris Cité, CNRS, Inserm, Institut Cochin
Florian Violon: Université Paris Cité, CNRS, Inserm, Institut Cochin
Thomas Foulonneau: Université Paris Cité, CNRS, Inserm, Institut Cochin
Yanis Bendjelal: Université Paris Cité, CNRS, Inserm, Institut Cochin
Philip Calvet: Université Paris Cité, CNRS, Inserm, Institut Cochin
Brigitte Izac: Université Paris Cité, CNRS, Inserm, Institut Cochin
Franck Letourneur: Université Paris Cité, CNRS, Inserm, Institut Cochin
Céline Bertholle: Université Paris Cité, CNRS, Inserm, Institut Cochin
Muriel Andrieu: Université Paris Cité, CNRS, Inserm, Institut Cochin
Rachel Onifarasoaniaina: Université Paris Cité, CNRS, Inserm, Institut Cochin
Maryline Favier: Université Paris Cité, CNRS, Inserm, Institut Cochin
Charlène Guitaut: ENS Paris-Saclay
Archibald Fraikin: ENS Paris-Saclay
Daniel Murat: Université Paris Cité, CNRS, Inserm, Institut Cochin
Roberta Armignacco: Université Paris Cité, CNRS, Inserm, Institut Cochin
Nesrine Benanteur: Université Paris Cité, CNRS, Inserm, Institut Cochin
Maria Francesca Birtolo: Université Paris Cité, CNRS, Inserm, Institut Cochin
Mathilde Sibony: Université Paris Cité, CNRS, Inserm, Institut Cochin
Karine Perlemoine: Université Paris Cité, CNRS, Inserm, Institut Cochin
Patricia Vaduva: Université Paris Cité, CNRS, Inserm, Institut Cochin
Lucas Bouys: Université Paris Cité, CNRS, Inserm, Institut Cochin
Fidéline Bonnet-Serrano: Université Paris Cité, CNRS, Inserm, Institut Cochin
Bertrand Dousset: Université Paris Cité, CNRS, Inserm, Institut Cochin
Martin Gaillard: Université Paris Cité, CNRS, Inserm, Institut Cochin
Eric Pasmant: Université Paris Cité, CNRS, Inserm, Institut Cochin
Maxime Barat: Université Paris Cité, CNRS, Inserm, Institut Cochin
Anthony Dohan: Université Paris Cité, CNRS, Inserm, Institut Cochin
Magalie Haissaguerre: CHU Haut Leveque
Antoine Tabarin: CHU Haut Leveque
Rossella Libé: Université Paris Cité, CNRS, Inserm, Institut Cochin
Laurence Guignat: Hôpital Cochin
Lionel Groussin: Université Paris Cité, CNRS, Inserm, Institut Cochin
Annabel Berthon: Université Paris Cité, CNRS, Inserm, Institut Cochin
Bruno Ragazzon: Université Paris Cité, CNRS, Inserm, Institut Cochin
Jérôme Bertherat: Université Paris Cité, CNRS, Inserm, Institut Cochin
Guillaume Assié: Université Paris Cité, CNRS, Inserm, Institut Cochin

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-63912-2

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