CANCER COMMUNICATIONS
Dlk1 is a novel adrenocortical stem/progenitor cell marker that predicts malignancy in adrenocortical carcinoma
Adrenocortical carcinoma (ACC) is a rare malignancy with no widely available biomarkers and commonly presents at later stages with a bleak prognosis [1]. Dysregulation of signaling pathways involved in the organogenesis and homeostasis of the adrenal cortex is implicated in its pathogenesis [2]. The paternally expressed, cleavable pro- tein delta-like non-canonical Notch ligand 1 (DLK1) is expressed in rat adrenocortical progenitor cells [3] and in clusters of relatively undifferentiated cells in the human adrenal gland [4]. Its expression is rare in most adult human tissues but has been reported across various can- cers, often associated with worse survival [5]. Here we define the role of DLK1 in adrenocortical development, self-renewal, and the development and progression of ACC.
Dlk1+ cells were present in both the capsule and cor- tex during embryonic development but became restricted to the capsule postnatally in both male and female mice (Supplementary Figure S1), with minimal over- lap in expression with Axin-2 (Wnt-active) cells, their early descendants, and platelet-derived growth factor receptor alpha (PDGFRa), a marker of mesenchymal stem/fibroblastic cells (Supplementary Figure S2). Dlk1 cells were rarely positive for Ki-67, whereas Gli1 expres- sion in the capsule, unlike Dlk1, remained high during development and throughout postnatal life (Supplemen- tary Figure S3). Genetic lineage tracing using inducible Dlk1CreERT2/+; RosatdTomato/+ mice showed that Dlk1+ cells functioned as adrenocortical stem cells during develop- ment (Figure 1A-F), but were largely dormant postnatally and inactive during postnatal adrenocortical remodeling (Supplementary Figure S4).
List of Abbreviations: ACC, Adrenocortical carcinoma; DLK1, Delta-like non-canonical Notch ligand 1; ENS@T, European Network for the Study of Adrenal Tumors; GDX, Gonadectomy; PDGFRa, Platelet-derived growth factor receptor alpha.
Katia Mariniello and James F.H. Pittaway contributed equally for this work (co-first authors).
Capsular-like cells are pathognomonic of subcapsu- lar hyperplasia (SH), a histological hallmark in mouse adrenals that occurs spontaneously in aged females and in certain strains/transgenic models after gonadectomy (GDX) [6]. SH foci are thought to represent a morphologi- cal continuum progressing toward adrenocortical tumors. Dlk1 was not expressed in SH or in subsequent tumors in two GDX mouse models (Supplementary Figure S5). Moreover, spontaneous SH foci in aged mice were nei- ther enriched in nor derived from Dlk1-expressing cells (Supplementary Figure S6), supporting the hypothesis that SH results from a de-differentiation event [7]. Interest- ingly, Dlk1 was re-expressed in an autochthonous mouse model of ACC, in which concomitant inactivation of Trp53 and activation of Ctnnb1, driven by the aldosterone syn- thase promoter (BPCre) [8], leads to ACC formation with high penetrance. In 23 tumor samples from 17 mice (9 female), Dlk1 expression was low or absent in benign and pre-malignant tumors, moderate in localized ACC, and higher in metastatic disease, both in the primary tumors and in lung metastases. There was a stepwise increase of Dlk1 expression with disease severity, and a positive cor- relation between Dlk1 expression and age (Figure 1G-H, Supplementary Figure S7). These results indicate that in the BPCre model, Dlk1, rather than marking the cell of ori- gin, is re-expressed in ACC, potentially conferring cancer stem cell characteristics.
In a prospective discovery cohort of 73 consecutive patients (26 male) undergoing adrenalectomy in London, UK (Supplementary Table S1), DLK1 expression was signif- icantly higher in ACC than in benign adrenal disease and normal adrenals (Supplementary Figure S8A). This finding was validated in a larger cohort from Würzburg, Germany, comprising 178 ACC tumor samples from 159 patients (53 male) (Supplementary Table S2). DLK1 expression was ubiquitous and heterogenous, with apparent clones of DLK1-positive cells, similar to those observed in BPCre mice. DLK1 expression was not correlated with age, sex, or tumor size and remained constant across different Euro- pean Network for the Study of Adrenal Tumors (ENS@T)
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
@ 2025 The Author(s). Cancer Communications published by John Wiley & Sons Australia, Ltd on behalf of Sun Yat-sen University Cancer Center.
(A)
(B)
P10
(C)
P38
(D
P38
(E)
P38
(F)
Ad.T
= ?
Cortex
ZG
…
Dlk1Cre
ZG
% RFP positive total cortical area
…
Tamoxifen
Analysis
Med
60
4
Į
Med
40
I
1
Cortex
E12.5
P10
P38
ZF
ZF
Ad.T
20
Kidney
0
RFP-DAPI
200 um
RFP-DAPI
200 um
RFP-Sf1
40 um
Med
RFP-Sf1
40 um
Med
0
P10
P38
BPCre
(G)
(H)
(K)
Recurrence free survival
(L)
Progression free survival - ENSAT I & II
250-
*
100
Probability of Survival
100
1
DLK1 Low (n=24)
200
Low
DLK1 High (n=33)
Dik1 H-score
150-
trend P = 0.0023 **
- Intermediate Low
Probability of Survival
Intermediate High
logrank HR=1.862, P = 0.0332*
50
100-
- High
50
1 mm
50
Low vs High
0
adj. P = 0.0366*
0
ACC
Metastatic Metastases
0
50
100
150
200
ACC
Human
Time after surgery (months)
(M)
*
Progression free survival - ENSAT III & IV
(1)
(J)
Recurrence/ metastasis
300-
P = 0.0091 **
DLK1 H-score
Probability of Survival
100
DLK1 Low (n=66)
250
= 0.5809
0
DLK1 High (n=58)
0
24
48
72
96
120
144
168
192
200-
Time after surgery (months)
logrank HR=1.159, P = 0.4210
=
150
No at risk:
50
20
12
9
6
3
2
2
1
100
20
8
4
3
2
1
1
50-
21
6
3
2
1
1
27
5
2
0
0
0
50
100
150
200
0
50
100
150
200
250
300
Time after surgery (months)
Primary tumor DLK1 H-score
(N)
(O)
BPCre
(P)
BCH-ACC3A sc
(Q)
H295R sc
(R)
Human (London)
Signal peptide
N
125-
125-
30-
20
EGF domain
Serum Dik1 (ng/ml)
100
Serum Dik1 (ng/ml)
100-
Serum DLK1 (ng/ml)
*
Serum DLK1 (ng/mL)
Uncertain malignant potential
75-
15
75-
20
TACE
50-
50-
10
10-
25-
25-
5
C
DLK1
0
80g Control
o
Tumor
0
0
Control
Tumor
Control
Tumor
0
Adenoma
ACC
(S)
Human (London)
(T)
Human (Würzburg)
Local recurrences
(U)
Human
(V)
Human (Würzburg)
20-
*
100-
Serum DLK1 (ng/ml)
*
**
25-
20-
Sensitivity%
80-
15-
Serum DLK1 (ng/ml)
London Würzburg
Serum DLK1 (ng/ml)
20-
15-
P = 0.00433 ** r = 0.8765
60-
10-
15-
10-
40-
..
10
20
5.
5-
5-
0
0
20
40
60
80
100
0
0
100% - Specificity%
Disease free
Primary tumor
Primary tumor & metastases
Recurrence post primary
0
0 50
100
150
200
250
Pre-op
Post-op
DLK1 H-score
surgery
(W)
(X)
(Y)
20
Significance
H295R
MUC1
TVBF7
CU-ACC1
Up-regulated (10)
kDa
2 20
2 20
H295R
2
20
2
2
Down-regulated (17)
DLK1
Inconclusive (5337)
800-
Not significant (13055)
15
EBP
18419 points 27 selected
-log10(P-value)
Colony Forming Units
SYP
55 -
600-
MSMO1
CLU
CTSA
35 -
10
FADS2
DHCR7
JUN
400
·
ATF3
DHCR24
CYP17A1
BNIP3
%
15 -
NDRG1 ENO2
EGR1
BNIP 3L
·
200-
PFKP
5
ANGPTL4
R4A1
O
DLK1
FOS
HILPDA
0
HK2
SPP1
37 -
DLK1+
DLK1-
CA9
ŠTO2
0
PFKFB4
GAPDH
-3
-1
0
2
3
log2(Fold change)
tumor stages, hormonal activity of tumors, Weiss score, and Ki-67% (Supplementary Figure S8B-H). As in BPCre mice, DLK1 expression was present in recurrent human disease and could clearly identify metastases from back- ground tissue. There was a significant positive correlation between DLK1 expression in primary tumors and in recur- rent/metastatic disease in the same patients (Figure 1I-J), marking DLK1 expression as a disease defining feature of disease progression.
In primary ACC (n = 88), higher DLK1 expression was associated with a stepwise increase in the risk of disease recurrence, which remained independently significant in multivariate Cox regression analysis (Figure 1K, Supple- mentary Table S3, Supplementary Figure S8I-J). In all ACC samples (n = 176), higher DLK1 expression trended toward
an increased risk of disease progression, though this did not reach statistical significance in multivariate Cox analy- sis (P= 0.079) (Supplementary Figure S8K, Supplementary Table S3). However, higher DLK1 expression was signifi- cantly associated with an increased risk of progression in ENS@T stage I & II disease (Figure 1L-M). These data sug- gest the metastatic potential of ACC may be influenced by DLK1 levels. RNA sequencing of the ACC cell line H295R, with DLK1 overexpression and knockdown, revealed that higher DLK1 expression was associated with lower expression of immune signaling gene set, suggesting that the carcinogenic role of DLK1 may, in part, be mediated through mechanisms associated with senescence- induced immune remodeling [9] (Supplementary Figure S9A-E).
FIGURE 1 Dlk1 is an adrenocortical stem/progenitor cell marker that predicts malignancy in adrenocortical carcinoma in mice and humans. (A) Schematic of Dlk1CreERT2/+; RosatdTomato/+ mice (Dlk1Cre) injected with tamoxifen for fate mapping experiments. Dlk1+ cells and their progeny were labelled with tdTomato (visualized with an anti-Red Fluorescence Protein [RFP] antibody) upon tamoxifen injection. (B-E) When dams were injected with tamoxifen at E12.5, and adrenals were analyzed at both P10 and P38, clusters and columns of RFP+/Sf1+ cells (representing Dlk1 progeny) spanned the entire width of the cortex in both males (D) and females (E). As expected, RFP was also detected in the medulla. (F) Dlk1 progeny were significantly decreased at P38 compared to P10, with females showing a small, non-significant trend toward more Dlk1 progeny than males. (G) In BPCre mice, Dlk1 expression increased stepwise from non-metastatic primary ACC to metastatic primary ACC and then to metastatic lesions. (H) Intense DLK1 expression was observed in lung metastases. (I) In humans, DLK1 expression was consistent in primary (upper left) and recurrent (lower right) tumors in the same patient. 19 secondary disease specimens were available from patients whose primary tumors were included in the study. (J) DLK1 expression level in secondary tumors positively correlated with those in primary tumors. (K) Categorizing DLK1 expression levels into quartiles (based on median and interquartile range values), higher DLK1 levels were associated with stepwise increase in the risk of disease recurrence (median RFS: low DLK1 = 32.5 months, low-intermediate DLK1 = 18.5 months, high-intermediate DLK1 = 15 months, and high DLK1 = 9 months). This was significant by the log-rank test for trend across the four groups (> = 9.263) and when comparing high versus low DLKI expression groups directly. (L) Higher DLK1 expression was associated with an increased risk of disease progression in ENSAT stage I & II disease (n = 57, median PFS: high DLK1 = 10 months versus low DLK1 = 27.5 months, HR 1.863, 95% CI = 1.038-3.340). (M) In ENSAT stage III & IV groups, median PFS was comparable (n = 121, high DLK1 = 6 months versus low DLK1 = 7 months, HR = 1.159, 95% CI = 0.793-1.694). There was no significant difference in mean Ki-67% between ENSAT stage I & II group (20.24 ± 16.68) and stage III & IV group (19.57 ± 16.28) in this cohort. (N) Illustration of DLK1 structure, highlighting the ectodomain cleaved by TACE. (O-Q) Serum Dlk1 levels were significantly higher in BPCre mice than in age-matched controls. This was also observed in subcutaneous tumor mouse models injected with BPCre tumor-derived BCH-ACC3A cells (P) and H295R human ACC cells (Q). (R) In humans, pre-operative serum DLK1 levels in the London prospective discovery cohort were significantly higher in ACC (16.81 ± 4.876ng/mL) than in benign adrenocortical adenomas (10.54 ± 4.417ng/mL). (S) Receiver operating characteristic (ROC) curve using all pre-operative values demonstrated that serum DLK1 predicted ACC diagnosis with high accuracy (AUC 0.824 ± 0.072, P < 0.001). (T) In the Würzburg validation cohort, serum DLK1 levels were higher in patients with ENSAT stage IV disease than in those with recurrent disease following primary surgery (11.46 ± 1.459ng/ml versus 6.749 ± 3.016ng/mL), disease-free patients (6.666 ± 2.855ng/ml), and patients with isolated primary tumors (11.46 ± 1.459ng/ml versus 7.357 ± 2.913ng/ml). (U) Following primary ACC resection, serum DLK1 levels significantly decreased compared to pre-operative levels (mean decrease = 6.568 ± 2.565ng/mL). (V) Pre-operative serum DLK1 levels significantly correlated with primary ACC DLK1 H-score in the same patients. (W) Volcano plot of differentially expressed genes in DLK1+ versus DLK1- tumor areas using spatial transcriptomics. Applying a fold-change cutoff of > 2 or < 2, 10 genes were significantly upregulated, and 17 genes were significantly downregulated. Among the 9 upregulated genes (excluding DLK1), 5 were involved in cholesterol synthesis (EBP, DHCR7, DHCR24, MSMO1) and fatty acids metabolism (FADS2). Other upregulated genes included those involved in steroidogenesis (CYP17A1), vesicular and cholesterol binding (SYP), and cathepsin (CTSA) and clusterin (CLU). Downregulated genes included pro-apoptotic genes (BNIP3, BNIP3L, NR4A1) and transcriptional regulators of differentiation (EGR1, FOS, JUN). (X) Western blot analysis showing increased DLK1 expression across the indicated ACC cell lines when cultured in 3D spheroid compared to 2D culture. (Y) H295R cells were fluorescence-activated cell sorted (FACS) into DLK1+ and DLK1- populations. DLK1+ cells generated significantly more colony-forming units than DLK1- cells after 21 days in culture. Data are displayed as individual points, with horizontal bars representing the mean. * P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.0001. Abbreviations: E, embryonic day; EGF, epidermal-like growth factor; Med, Medulla; P, postnatal day; PFS, progression-free survival; RFS, recurrence-free survival; sc, subcutaneous; TACE, TNFa converting enzyme.
DLK1 has a cleavable ectodomain that is detectable in serum. Serum Dlk1 levels were significantly higher in BPCre mice (compared to age-matched controls) and in two subcutaneous tumor mouse models: one using the BPCre tumor-derived cell line BCH-ACC3A [10] and another injected with H295R cells (Figure 1N-Q). In all cases, there was a strong positive correlation between tumor size and serum DLK1 levels (Supplementary Figure S10). In humans, pre-operative serum DLK1 levels were significantly higher in ACC than in benign adrenocorti- cal adenomas in the London cohort and could predict the diagnosis of ACC with high sensitivity and speci- ficity (Figure 1R-S). This finding was validated in the German cohort, where significantly higher serum DLK1 levels were observed in patients with a greater disease bur- den (Figure 1T, Supplementary Table S4). As in tissue, serum DLK1 levels did not correlate with other prognos- tic or clinicopathological features (Supplementary Figure S11A-F). Post-operative blood samples showed a significant reduction in DLK1 levels after tumor resection (Figure 1U). Pre-operative serum DLK1 levels positively correlated with tissue DLK1 expression in both cohorts (Figure 1V, Supple- mentary Figure S11G). These findings indicate that serum DLK1 is derived from ACC, with levels reflecting the DLK1 expression of the primary tumor and the extent of disease.
Spatial whole-transcriptome profiling was performed on DLK1+ and DLK1- regions within four human ACCs. Sur- prisingly, steroid biosynthesis was the gene ontology path- way most enriched in the DLK1+ group, consistent with the upregulation of cholesterol synthesis genes, suggesting that DLK1+ areas have higher steroidogenic potential than DLK1- areas (Figure 1W, Supplementary Figures S12-S13). This finding was further supported by increased expres- sion of adrenal differentiation genes with higher DLK1 dosage in the H295R transcriptomic data (Supplemen- tary Figure S9F-H). To further investigate this apparent paradox of enhanced steroidogenic potential in ACC cells expressing an adrenocortical stem cell marker, four dif- ferent human ACC cell lines (H295R, MUC-1, TVBF7 and CU-ACC1) and one mouse ACC cell line (BCH-ACC3A) were cultured as spheroids. DLK1 expression was signifi- cantly enhanced in 3D versus 2D culture in H295R, TVBF7, and CU-ACC1, and interestingly, de novo expression of DLK1 protein was observed in MUC-1 (Figure 1X, Sup- plementary Figure S14A-F). Liquid chromatography with tandem mass spectrometry revealed that 3D spheroids had significantly increased output of steroids compared to 2D cells in H295R, CU-ACC1, and BCH-ACC3A, with a trend toward increased steroidogenesis in MUC-1 and TVBF7 (Supplementary Table S5). Fluorescence-activated cell sorting showed that DLK1+ cells generated significantly more colony-forming units than DLK1- populations after
21 days in culture (Figure 1Y, Supplementary Figure S14G-H). These findings suggest that ACC cells expressing a bona fide adrenocortical stem cell marker possess superior steroidogenic potential while retaining some progenitor cell features, providing a possible explanation for the negative prognostic impact of DLK1 expression in ACC.
These data define Dlk1 as a novel adrenocortical stem/progenitor cell marker with a role in both adrenocor- tical organogenesis and malignancy development. Expres- sion data from mice and human ACC indicate that DLK1 is associated with increased malignancy and tumor aggressiveness. Furthermore, DLK1 holds promise as a biomarker for the diagnosis, prognosis, and follow-up of patients with ACC, particularly through serum measure- ments using a benchtop assay. Further larger prospective studies are needed to confirm this role, along with investi- gations into DLK1 as a potential therapeutic target in ACC, given its preferential expression in this malignancy.
AUTHOR CONTRIBUTIONS
Conceptualization: Leonardo Guasti, James F.H. Pittaway, and Katia Mariniello. Methodology: Leonardo Guasti, James F.H. Pittaway, Katia Mariniello, Barbara Altieri, Irene Hadjidemetriou, Silviu Sbiera, Matthias Kroiss, Mar- tin Fassnacht, William M. Drake, Kleiton Silva Borges, and David T. Breault. Validation: Kleiton Silva Borges, Claudio Ribeiro, Katia Mariniello, James F.H. Pittaway, Barabara Altieri, Jiang A. Lim, David T. Breault, David S. Tourigny and Charlotte Hall. Formal analysis: James F.H. Pittaway, Katia Mariniello, Barbara Altieri, and Kleiton Silva Borges. Investigation: Gerard Ruiz-Babot, Oliver Rayner, David R. Taylor, James F.H. Pittaway, Katia Mariniello, Barbara Altieri, Leonardo Guasti, Silviu Sbiera, Carles Gaston- Massuet, and Emanuel Rognoni. Resources: Sandra Sigala, Andrea Abate, Mariangela Tamburello, Katja Kiseljak- Vassiliades, Margaret Wierman, Laila Parvanta, Tarek E. Abdel-Aziz, Teng-Teng Chung, Aimee Di Marco, Fausto Palazzo, Celso E. Gomez-Sanchez, Constanze Hantel, Julie Foster, Julie Cleaver, Jane Sosabowski, Nafis Rahman, Milena Doroszko, and Cristina L. Ronchi. Data cura- tion: James F.H. Pittaway, Katia Mariniello, and Leonardo Guasti. Writing-original draft: James F.H. Pittaway, Katia Mariniello, and Leonardo Guasti. Writing-review and edit- ing: all authors. Supervision: Leonardo Guasti, William M. Drake, Martin Fassnacht, Matthias Kroiss, David T. Breault. Project administration: Leonardo Guasti.
ACKNOWLEDGEMENTS
We would like to thank all the patients, both in UK and in Germany, who consented to the use of their samples and clinical information in this study, especially the family
of Jo-Anne Baldock, who donated money to the depart- ment for a piece of equipment to further research in adrenocortical carcinoma.
CONFLICT OF INTEREST STATEMENT
The authors declare no potential conflicts of interest regarding the research, authorship, and/or publication of this article.
FUNDING INFORMATION
This work was supported by the MRC (MR/X021017/1, MR/S022155/1), BBSRC (BB/V007246/1), Barts Charity (MGU0436), Rosetrees Trust (M355-F1), The Medical College of Saint Bartholomew’s Hospital Trust, the German Research Foundation (Deutsche Forschungsge- meinschaft, 314061271), and the National Institutes of Health Physician-Scientist Career Development Award (R01DK123694).
DATA AVAILABILITY STATEMENT
In all graphs, data are presented as individual values for transparency. Spatial transcriptomic and cell line tran- scriptomic data have been deposited in the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) under accession numbers GSE277486 and GSE286393, respectively.
ETHICS APPROVAL AND CONSENT TO PARTICIPATE
Human adrenal specimens were collected from patients undergoing surgery at St Bartholomew’s, University Col- lege and Hammersmith Hospitals, London, after obtaining written informed consent from participants and in accor- dance with the study protocol Genetics of endocrine tumors (REC: 06/Q0104/133). In Germany, all tissue was collected under the ENS@T research ethical agree- ment (No. 88/11) at the Universitätsklinikum Würzburg. All patients provided informed consent. All clinical data were collected through the ENS@T database (reg- istry.ensat.org).
Katia Mariniello1 James F. H. Pittaway1 İD Barbara Altieri2
Kleiton Silva Borges3,4 [D Irene Hadjidemetriou1 Claudio Ribeiro3,4
Gerard Ruiz-Babot3,5 David S. Tourigny6 Jiang A. Lim1 Julie Foster7 Julie Cleaver7
Jane Sosabowski7 Nafis Rahman8 Milena Doroszko8 Constanze Hantel9 Sandra Sigala10 Andrea Abate10 Mariangela Tamburello10 Katja Kiseljak-Vassiliades11,12 Margaret Wierman11,12 Charlotte Hall1 Laila Parvanta13 Tarek E. Abdel-Aziz14 Teng-Teng Chung15 Aimee Di Marco16 Fausto Palazzo16 Celso E. Gomez-Sanchez17 David R. Taylor18 Oliver Rayner18 Cristina L. Ronchi19 Carles Gaston-Massuet1 Silviu Sbiera2 William M. Drake1 Emanuel Rognoni20 Matthias Kroiss2,21 David T. Breault3,4 Martin Fassnacht2 Leonardo Guasti1
1Centre for Endocrinology, William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, UK
2 Division of Endocrinology and Diabetes, Dept. of Medicine, University Hospital, University of Würzburg, Würzburg, Germany
3 Division of Endocrinology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
4 Harvard Stem Cell Institute, Cambridge, Massachusetts, USA 5 Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technical, University Dresden, Dresden, Germany
6 School of Mathematics, University of Birmingham, Birmingham, UK
7 Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, UK
8 Institute of Biomedicine, University of Turku, Turku, Finland
9 Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ) and University of Zurich (UZH), Zurich, Switzerland
10 Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy 11 Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA
12 Division of Endocrinology, Metabolism and Diabetes at Rocky Mountain Regional Veterans Affair Medical Center, Washington, District of Columbia, USA
13 Department of Surgery, St Bartholomew’s Hospital, West Smithfield, London, UK
14 Department of Surgery, University College London Hospitals NHS Foundation Trust, London, UK
15 Department of Endocrinology, University College London Hospitals NHS Foundation Trust, London, UK 16 Department of Endocrine and Thyroid Surgery, Hammersmith Hospital, Imperial College London, London, UK
17 Endocrine Section, G.V. (Sonny) Montgomery VA Medical Center and the Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi, USA
18 Department of Clinical Biochemistry (Synnovis Analytics), King’s College Hospital, London, UK 19 Institute of Metabolism and System Research College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK 20 Centre for Cell Biology & Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK 21 Department of Internal Medicine IV, LMU University Hospital, LMU Munich, München, Germany
Correspondence
James F. H. Pittaway, Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.
Email: j.pittaway@qmul.ac.uk
ORCID
James F. H. Pittaway [ https://orcid.org/0000-0003-0112- 8463 Kleiton Silva Borges [ https://orcid.org/0000-0003-0356- 922X
REFERENCES
1. Fassnacht M, Dekkers OM, Else T, Baudin E, Berruti A, de Krijger R, et al. European Society of Endocrinology Clini- cal Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Net- work for the Study of Adrenal Tumors. Eur J Endocrinol. 2018;179(4):G1-G46.
2. Pittaway JFH, Guasti L. Pathobiology and genetics of adrenocor- tical carcinoma. J Mol Endocrinol. 2019;62(2):R105-R19.
3. Guasti L, Cavlan D, Cogger K, Banu Z, Shakur A, Latif S, et al. Dlk1 up-regulates Gli1 expression in male rat adrenal cap- sule cells through the activation of beta1 integrin and ERK1/2. Endocrinology. 2013;154(12):4675-84.
4. Hadjidemetriou I, Mariniello K, Ruiz-Babot G, Pittaway J, Mancini A, Mariannis D, et al. DLK1/PREF1 marks a novel cell population in the human adrenal cortex. J Steroid Biochem Mol Biol. 2019;193:105422.
5. Pittaway JFH, Lipsos C, Mariniello K, Guasti L. The role of delta- like non-canonical Notch ligand 1 (DLK1) in cancer. Endocr Relat Cancer. 2021;28(12):R271-R87.
6. Basham KJ, Hung HA, Lerario AM, Hammer GD. Mouse models of adrenocortical tumors. Mol Cell Endocrinol. 2016;421:82-97.
7. Mathieu M, Drelon C, Rodriguez S, Tabbal H, Septier A, Damon-Soubeyrand C, et al. Steroidogenic differentiation and PKA signaling are programmed by histone methyltransferase EZH2 in the adrenal cortex. Proc Natl Acad Sci U S A. 2018;115(52):E12265-E74.
8. Borges KS, Pignatti E, Leng S, Kariyawasam D, Ruiz-Babot G, Ramalho FS, et al. Wnt/beta-catenin activation cooperates with loss of p53 to cause adrenocortical carcinoma in mice. Oncogene. 2020;39(30):5282-91.
9. Warde KM, Smith LJ, Liu L, Stubben CJ, Lohman BK, Willett PW, et al. Senescence-induced immune remodeling facilitates metastatic adrenal cancer in a sex-dimorphic manner. Nat Aging. 2023;3(7):846-65.
10. Mohan DR, Borges KS, Finco I, LaPensee CR, Rege J, Solon AL, et al. beta-Catenin-Driven Differentiation Is a Tissue- Specific Epigenetic Vulnerability in Adrenal Cancer. Cancer Res. 2023;83(13):2123-41.
SUPPORTING INFORMATION
Additional supporting information can be found online in the Supporting Information section at the end of this article.