Dlk1 is a novel adrenocortical stem/progenitor cell marker that predicts malignancy in adrenocortical carcinoma
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ABSTRACT:
PROVIDER: PRJNA1162506 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30714500_1.fastq.gz | Fastqsanger.gz | |||
| SRR30714500_2.fastq.gz | Fastqsanger.gz | |||
| SRR30714501_1.fastq.gz | Fastqsanger.gz | |||
| SRR30714501_2.fastq.gz | Fastqsanger.gz | |||
| SRR30714502_1.fastq.gz | Fastqsanger.gz |
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Project description:Adrenocortical carcinoma (ACC) is characterized by disruption of tissue development and homeostatic pathways. Here, using genetic fate mapping and murine 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. DLK1 expression is widespread in human ACC samples and independently influences recurrence-free survival. Spatial transcriptomic analysis has identified DLK1 positive ACC cells to have increased steroidogenic potential, a finding also observed in both human and murine ACC cell lines. Additionally, the cleavable DLK1 ectodomain is detectable in patients’ serum and effectively distinguishes ACC from other adrenal pathologies, offering potential diagnostic and follow-up utility for ACC patients. These data demonstrate a prognostic role for DLK1 in ACC, elucidate its hierarchical expression in homeostasis and cancer and suggest its utility as a biomarker in this malignancy.
2024-10-21 | GSE277486 | GEO
Project description:Dlk1 is a novel adrenocortical stem/progenitor cell marker that predicts malignancy in adrenocortical carcinoma [ssRNA-Seq]
| PRJNA1209063 | ENA
Project description:Adrenocortical carcinoma (ACC) is characterized by disruption of tissue development and homeostatic pathways. Here, using genetic fate mapping and murine 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. DLK1 expression is widespread in human ACC samples and independently influences recurrence-free survival. Spatial transcriptomic analysis has identified DLK1 positive ACC cells to have increased steroidogenic potential, a finding also observed in both human and murine ACC cell lines. Additionally, the cleavable DLK1 ectodomain is detectable in patients’ serum and effectively distinguishes ACC from other adrenal pathologies, offering potential diagnostic and follow-up utility for ACC patients. These data demonstrate a prognostic role for DLK1 in ACC, elucidate its hierarchical expression in homeostasis and cancer and suggest its utility as a biomarker in this malignancy.
2025-03-01 | GSE286393 | GEO
Project description: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.
| S-EPMC11370565 | biostudies-literature
Project description:Cancer immunotherapies have produced remarkable results in B-cell malignancies; however, optimal cell surface targets for many solid cancers remain elusive. Here, we present an integrative proteomic, transcriptomic, and epigenomic analysis of tumor specimens along with normal tissues to identify biologically relevant cell surface proteins that can serve as immunotherapeutic targets for neuroblastoma, the often fatal childhood cancer of the developing nervous system. We apply this approach to human-derived cell lines (N=9) and cell/patient-derived xenograft (N=12) models of neuroblastoma. Plasma membrane-enriched mass spectrometry identified 1,461 cell surface proteins in cell lines and 1,401 in xenograft models, respectively. Additional proteogenomic analyses revealed 71 high-confidence candidate immunotherapeutic targets and we prioritized Delta-like canonical notch ligand 1 (DLK1) for further study. High expression of DLK1 directly correlated with the presence of a super-enhancer spanning the DLK1 locus. Robust cell surface expression of DLK1 was validated by immunofluorescence, flow cytometry, and immunohistochemistry. Short hairpin RNA mediated silencing of DLK1 in neuroblastoma cells resulted in increased cellular differentiation. ADCT-701, a DLK1-targeting antibody-drug conjugate (ADC), showed potent and specific cytotoxicity in DLK1-expressing neuroblastoma xenograft models. Finally, we also found that DLK1 is highly expressed in several adult cancer types including adrenocortical carcinoma (ACC), pheochromocytoma/paraganglioma (PCPG) and small cell lung cancer (SCLC) suggesting potential clinical benefit beyond neuroblastoma. A clinical trial has been developed for evaluating ADCT-701 in neuroendocrine tumors in adults (https://www.clinicaltrials.gov/study/NCT06041516?term=adct-701&rank=1). Therefore, comprehensive characterization of cancer surfaceomes can provide biologically relevant immunotherapy targeting strategies.
2024-10-23 | PXD047474 | Pride
Project description:While immunotherapeutic targeting of cell surface proteins is an increasingly effective cancer therapy, identification of new surface proteins, particularly those with biological importance, is critical. Here, we uncover delta-like non-canonical Notch ligand 1 (DLK1) as a cell surface protein with limited normal tissue expression and high expression in multiple refractory adult metastatic cancers including small cell lung cancer (SCLC) and adrenocortical carcinoma (ACC), a rare cancer with few effective therapies. In ACC, ADCT-701, a DLK1 targeting antibody-drug conjugate (ADC), shows in vitro and in vivo activity but is overall limited due to high expression and activity of the drug efflux protein ABCB1 (MDR1, P-glycoprotein). In contrast, ADCT-701 induces complete responses in DLK1+ ACC and SCLC in vivo models with low or no ABCB1 expression. Genetic deletion of DLK1 in ACC dramatically downregulates ABCB1 and increases ADC payload and chemotherapy sensitivity through NOTCH1-mediated transdifferentiation. This work identifies DLK1 as an immunotherapeutic target that regulates tumor cell plasticity and chemoresistance in ACC and supports an active phase I clinical trial targeting DLK1 with an ADC in ACC and neuroendocrine neoplasms (NCT06041516).
2025-05-19 | GSE294644 | GEO
Project description:Differential diagnosis of adrenocortical adenoma and carcinoma is of pivotal clinical relevance, as the prognosis and clinical management of benign and malignant adrenocortical tumours is entirely different. Circulating microRNAs are promising biomarker candidates of malignancy in several tumours. In the present study we investigate circulating microRNAs in adrenocortical tumours and to evaluate their potential applicability as biomarkers of malignancy.
2013-11-19 | GSE49674 | GEO
Project description:Differential diagnosis of adrenocortical adenoma and carcinoma is of pivotal clinical relevance, as the prognosis and clinical management of benign and malignant adrenocortical tumours is entirely different. Circulating microRNAs are promising biomarker candidates of malignancy in several tumours. In the present study we investigate circulating microRNAs in adrenocortical tumours and to evaluate their potential applicability as biomarkers of malignancy. For the miRNA profiling, 8 preoperative plasma samples obtained from patients with adrenocortical adenomas and carcinomas and were studied by microarray.
2013-11-19 | E-GEOD-49674 | biostudies-arrayexpress
Project description:Adrenocortical carcinoma (ACC) is an aggressive malignancy with a low but variable overall survival rate. Even after complete tumor resection, over half of patients develop recurrent disease. Long noncoding RNAs (lncRNAs) have been found to be involved in cancer initiation/progression and as markers of cancer prognosis. The role of lncRNAs in ACC is poorly understood. Thus, in this study we performed lncRNA expression profiling in ACC, adrenocortical adenoma (ACA) and normal adrenal cortex (NAC). Total RNA was extracted from fresh frozen tissue samples (11 ACA, nine ACC and five NAC samples) with histopathological confirmed diagnosis. ArrayStar Human LncRNA/mRNA Expression Microarray V3.0 was used for transcriptome analysis. Differentially expressed lncRNAs were validated using TaqMan real-time quantitative PCR in a validation cohort including an additional 10 ACCs. The ACC dataset from the Cancer Genome Atlas (TCGA) project was used to evaluate the prognostic utility of lncRNAs found to be differentially expressed in ACC. Survival curves were plotted by Kaplan-Meier analysis, and differences in survival rates were assessed using a log-rank test. P < 0.05 was considered significant. Gene Set Enrichment Analysis (GSEA) was performed to identify lncRNA-associated biological signaling pathways. Unsupervised hierarchical and heat map clustering showed distinct clustering of ACC samples compared with NAC and ACA samples by lncRNA expression profiles. A total of 874 lncRNAs were differentially expressed between ACC and NAC, including known carcinogenesis-related lncRNAs such as HOTTIP, HOXA11-AS1, CRNDE, LINC00271 and TBXAS1. One thousand seventy-six lncRNAs were differentially expressed between ACC and ACA. LINC00271 was a prognostic marker, with patients with low LINC00271 expression surviving significantly shorter than patients with a high LINC00271 expression. Median survival time (MST) for the low-expression group was 1788 days, whereas the MST was not reached for the high-expression group (P < 0.019). Importantly, low LINC00271 expression was positively associated with WNT signaling, cell cycle, chromosome segregation and tissue morphogenesis pathways. ACC has a distinct lncRNA expression profile. LINC00271 is a prognostic marker in ACC and is involved in biological pathways commonly dysregulated in ACC.
2019-07-01 | GSE124531 | GEO
Project description:Adrenocortical carcinoma (ACC) is an aggressive malignancy with high rates of recurrence following surgical resection. Long noncoding RNAs (lncRNAs) play an important role in cancer development. Pathogenesis of adrenal tumours has been characterised by mRNA, microRNA and methylation expression signatures but it is unknown if this extends to lncRNAs. We sought to describe lncRNA expression signatures in adrenocortical carcinoma (ACC), adrenal cortical adenoma (ACA) and normal adrenal cortex (NAC). RNA was extracted from freshly frozen tissue with confirmation of diagnosis by histopathology. Focused lncRNA and mRNA transcriptome analysis was performed using the ArrayStar Human LncRNA V3.0 microarray. Differentially expressed lncRNAs were validated using qRT-PCR.
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