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, D. De Murat, Roberta Armignacco, Nesrine Benanteur, Maria Francesca Birtolo, Mathilde Sibony, Karine Perlemoine, Patricia Vaduva, Lucas Bouys, Fidéline Bonnet-Serrano, B. Dousset, Martin Gaillard, Éric Pasmant, Maxime Barat, Anthony Dohan, Magalie Haissaguerre, Antoine Tabarin, Rossella Libé, Laurence Guignat, Lionel Groussin, Annabel Berthon, Bruno Ragazzon, Jérôme Bertherat, Guillaume Assié
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.