
==== Front
bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.08.22.609117
preprint
1
Article
Dlk1 is a novel adrenocortical stem/progenitor cell marker that predicts malignancy in adrenocortical carcinoma
Mariniello Katia
Pittaway James F.H. http://orcid.org/0000-0003-0112-8463

Altieri Barbara
Borges Kleiton Silva
Hadjidemetriou Irene
Ribeiro Claudio
Ruiz-Babot Gerard
Lim Jiang A.
Foster Julie
Cleaver Julie
Sosabowski Jane
Rahman Nafis
Doroszko Milena
Hantel Constanze
Sigala Sandra
Abate Andrea
Tamburello Mariangela
Kiseljak-Vassiliades Katja
Wierman Margaret
Parvanta Laila
Abdel-Aziz Tarek E.
Chung Teng-Teng
Marco Aimee Di
Palazzo Fausto
Gomez-Sanchez Celso E.
Taylor David R.
Rayner Oliver
Ronchi Cristina L.
Gaston-Massuet Carles
Sbiera Silviu
Drake William M.
Rognoni Emanuel
Kroiss Matthias
Breault David T.
Fassnacht Martin
Guasti Leonardo
22 8 2024
2024.08.22.609117https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://biorxiv.org/lookup/doi/10.1101/2024.08.22.609117
nihpp-2024.08.22.609117.pdf
Abstract

Disruption of processes involved in tissue development and homeostatic self-renewal is increasingly implicated in cancer initiation, progression, and recurrence. The adrenal cortex is a dynamic tissue that undergoes life-long turnover. Here, using genetic fate mapping and murine adrenocortical carcinoma (ACC) models, we have identified a population of adrenocortical stem cells that express delta-like non-canonical Notch ligand 1 (DLK1). These cells are active during development, near dormant postnatally but are re-expressed in ACC. In a study of over 200 human ACC samples, we have shown DLK1 expression is ubiquitous and is an independent prognostic marker of recurrence-free survival. Paradoxically, despite its progenitor role, spatial transcriptomic analysis has identified DLK1 expressing cell populations to have increased steroidogenic potential in human ACC, a finding also observed in four human and one murine ACC cell lines. Finally, the cleavable DLK1 ectodomain is measurable in patients’ serum and can discriminate between ACC and other adrenal pathologies with high sensitivity and specificity to aid in diagnosis and follow-up of ACC patients. These data demonstrate a prognostic role for DLK1 in ACC, detail its hierarchical expression in homeostasis and oncogenic transformation and propose a role for its use as a biomarker in this malignancy.

Graphical abstract

Statement of significance

This study presents DLK1 as a novel biomarker in ACC with opportunities for use in the diagnosis, prognosis and longitudinal follow up of patients. DLK1, a marker of adrenocortical stem cells, is re-expressed in ACC, is measurable in patients’ serum and is associated with increased malignancy.
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