Nature Communications

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

A Anne Jouinot Y Yoann Martin F Florian Violon T Thomas Foulonneau Y Yanis Bendjelal P Philip Calvet B Brigitte Izac (CNRS, INSERM, Institut Cochin, Université Paris Cité) F Franck Letourneur C Céline Bertholle M Muriel Andrieu (Université Paris Cité, CNRS UMR 8104, Inserm U1016) R Rachel Onifarasoaniaina M Maryline Favier C Charlène de Guitaut A Archibald Fraikin D Daniel de Murat R Roberta Armignacco N Nesrine Benanteur M Maria Francesca Birtolo M Mathilde Sibony K Karine Perlemoine P Patricia Vaduva L Lucas Bouys F Fidéline Bonnet-Serrano B Bertrand Dousset M Martin Gaillard E Eric Pasmant M Maxime Barat A Anthony Dohan M Magalie Haissaguerre A Antoine Tabarin R Rossella Libé L Laurence Guignat L Lionel Groussin A Annabel Berthon B Bruno Ragazzon J Jérôme Bertherat G Guillaume Assié

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.

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Article Details

Volume / Issue Vol. 16, Issue 1
Published October 06, 2025
ISSN 2041-1723
Publisher Nature Portfolio

Journal Info

Nature Communications

Nature Portfolio
ISSN: 2041-1723 Open Access Life Sciences

Authors (37)

A

Anne Jouinot

Y

Yoann Martin

F

Florian Violon

T

Thomas Foulonneau

Y

Yanis Bendjelal

P

Philip Calvet

B

Brigitte Izac

CNRS, INSERM, Institut Cochin, Université Paris Cité

F

Franck Letourneur

C

Céline Bertholle

M

Muriel Andrieu

Université Paris Cité, CNRS UMR 8104, Inserm U1016

R

Rachel Onifarasoaniaina

M

Maryline Favier

C

Charlène de Guitaut

A

Archibald Fraikin

D

Daniel de Murat

R

Roberta Armignacco

N

Nesrine Benanteur

M

Maria Francesca Birtolo

M

Mathilde Sibony

K

Karine Perlemoine

P

Patricia Vaduva

L

Lucas Bouys

F

Fidéline Bonnet-Serrano

B

Bertrand Dousset

M

Martin Gaillard

E

Eric Pasmant

M

Maxime Barat

A

Anthony Dohan

M

Magalie Haissaguerre

A

Antoine Tabarin

R

Rossella Libé

L

Laurence Guignat

L

Lionel Groussin

A

Annabel Berthon

B

Bruno Ragazzon

J

Jérôme Bertherat

G

Guillaume Assié

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