Mariniello Katia, Pittaway James F H, 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, Di Marco Aimee, 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
Centre for Endocrinology, William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, UK.
Division of Endocrinology and Diabetes, Dept. of Medicine, University Hospital, University of Würzburg, 97080 Würzburg, Germany.
bioRxiv. 2024 Aug 22:2024.08.22.609117. doi: 10.1101/2024.08.22.609117.
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.
组织发育和稳态自我更新过程的破坏越来越多地与癌症的发生、发展和复发有关。肾上腺皮质是一个经历终身更新的动态组织。在这里，我们使用基因命运图谱和小鼠肾上腺皮质癌（ACC）模型，鉴定出了一群表达δ样非经典Notch配体1（DLK1）的肾上腺皮质干细胞。这些细胞在发育过程中活跃，出生后近乎休眠，但在ACC中重新表达。在一项对200多个人类ACC样本的研究中，我们发现DLK1表达普遍存在，并且是无复发生存的独立预后标志物。矛盾的是，尽管其具有祖细胞作用，但空间转录组分析发现，在人类ACC中，表达DLK1的细胞群具有增强的类固醇生成潜力，这一发现也在四种人类和一种小鼠ACC细胞系中观察到。最后，可裂解的DLK1胞外结构域在患者血清中可检测到，并且能够以高灵敏度和特异性区分ACC与其他肾上腺疾病，有助于ACC患者的诊断和随访。这些数据证明了DLK1在ACC中的预后作用，详细阐述了其在稳态和致癌转化中的分级表达，并提出了其作为这种恶性肿瘤生物标志物的作用。
