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 de Guitaut
- Archibald Fraikin
- Daniel de 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
- Guillaume Assié
2025-10-06
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.