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Abstract Context Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with poor prognosis in advanced stages. While therapies targeting the checkpoint molecules programmed cell death 1 (PD-1), its ligand PD-L1, and the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) have revolutionized treatment in many cancers, the results in ACCs were heterogeneous. Objective Their expression in ACC has not been systematically studied and might explain the variable response to immune checkpoint inhibitors. Methods The expression of PD-1, PD-L1 and CTLA-4 was examined in 162 tumor samples from 122 patients with ACC by immunohistochemistry (threshold of >1%) and correlated with tumoral T lymphocyte infiltration and clinical endpoints. Finally, univariate and multivariate analyses of progression-free and overall survival were performed. Results PD-1 and PD-L1 were expressed in 26.5% and 24.7% of samples, respectively, with low expression in most tumor samples (median positive cells: 2.1% and 21.7%). In contrast, CTLA-4 expression was observed in 52.5% of ACC with a median of 38.4% positive cells. Positive PD-1 expression was associated with longer progression-free survival (HR 0.50, 95% CI 0.25-0.98, P = .04) even after considering prognostic factors. In contrast, PD-L1 and CTLA-4 did not correlate with clinical outcome. Additionally, PD-1 and PD-L1 expression correlated significantly with the amount of CD3+, CD4+, FoxP3+, and CD8+ T cells. Conclusion The heterogeneous expression of PD1, PD-L1, and CTLA-4 in this large series of well-annotated ACC samples might explain the heterogeneous results of the immunotherapies in advanced ACC. In addition, PD-1 expression is a strong prognostic biomarker that can easily be applied in routine clinical care and histopathological assessment.

Adrenocortical carcinomas (ACCs) are rare and highly malignant cancers associated with poor survival of patients. Currently, mitotane, a nonspecific derivative of the pesticide DDT (1,1-(dichlorobiphenyl)-2,2-dichloroethane), is used as the standard treatment, but its mechanism of action in ACCs remains elusive. Here we demonstrate that the human ACC NCI-H295R cell line is remarkably sensitive to induction of ferroptosis, while mitotane does not induce this iron-dependent mode of regulated necrosis. Supplementation with insulin, transferrin, and selenium (ITS) is commonly used to keep NCI-H295R cells in cell culture. We show that this supplementation prevents spontaneous ferroptosis, especially when it contains polyunsaturated fatty acids (PUFAs), such as linoleic acid. Inhibitors of apoptosis (zVAD, emricasan) do not prevent the mitotane-induced cell death but morphologically prevent membrane blebbing. The expression of glutathione peroxidase 4 (GPX4) in H295R cells, however, is significantly higher when compared to HT1080 fibrosarcoma cells, suggesting a role for ferroptosis. Direct inhibition of GPX4 in H295R cells led to high necrotic populations compared to control, while cotreatment with ferrostatin-1 (Fer-1) completely reverted ferroptosis. Interestingly, the analysis of public databases revealed that several key players of the ferroptosis pathway are hypermethylated and/or mutated in human ACCs. Finally, we also detected that growth hormone-releasing hormone (GHRH) antagonists, such as MIA602, kill H295R cells in a nonapoptotic manner. In summary, we found elevated expression of GPX4 and higher sensitivity to ferroptosis in ACCs. We hypothesize that instead of treatment with mitotane, human adrenocortical carcinomas may be much more sensitive to induction of ferroptosis.

Background Serum inflammation-based scores can predict clinical outcome in several cancer types, including adrenocortical carcinoma (ACC). It is unclear whether the extent of inflammation-based scores alterations in ACC reflects malignancy, steroid excess, or both. Methods We investigated a large retrospective cohort of adrenocortical adenomas (ACA, n  = 429) and ACC ( n  = 61) with available baseline full blood count and hormonal evaluation. We examined the relationship between different inflammation-based scores [neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammation index (SII), and prognostic nutrition index (PNI)] and both malignancy and steroid secretion patterns. Results All inflammation-based scores differed between ACC and ACA: patients with ACC had higher NLR, PLR, SII and lower LMR and PNI levels compared to ACA (all p values < 0.001). NLR showed a positive correlation with cortisol levels after overnight 1 mg-dexamethasone suppression test (1 mg-DST), both in ACC and ACA ( p  < 0.01). The ROC curve analysis determined NLR > 2.6 as the best cut-off to discriminate ACC from ACA [AUC = 0.846, p  < 0.01]. At multivariable analysis, NLR > 2.6 was independently associated with ACC, 1 mg-DST cortisol levels and age, but not with tumour size. Considering the ACC, NLR and SII were higher and PNI was lower in patients with cortisol excess compared to those without cortisol excess ( p  = 0.002, p  = 0.007, and p  = 0.044 respectively). Finally, LMR and NLR differed between inactive-ACC ( n  = 10) and inactive-ACA ( n  = 215) ( p  = 0.040 and p  = 0.031, respectively). Conclusion Inflammation-based scores are related to steroid secretion both in ACC and ACA. ACCs present a higher grade of inflammation regardless of their hormonal secretion, likely as a feature of malignancy itself.

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). Adrenocortical carcinoma (ACC) has limited treatment options and few tumor-specific targets. Here the authors report that the Notch ligand DLK1 is highly expressed in ACC acting as a regulator of tumor cell plasticity and chemoresistance, and that DLK1 can be targeted with an antibody drug conjugate.

Adrenal tumors, such as adrenocortical carcinoma (ACC), adrenocortical adenoma (ACA), and pheochromocytoma (PCC) are complex diseases with unclear causes and treatments. Mitochondria and mitochondrial-derived peptides (MDPs) are crucial for cancer cell survival. The primary aim of this study was to analyze samples from different adrenal diseases, adrenocortical carcinoma, adrenocortical adenoma, and pheochromocytoma, and compare them with normal adrenal tissue to determine whether the expression levels of the mitochondrial open reading frame of the 12S rRNA type-c (MOTS-c) gene and protein vary between different types of adrenal tumors compared to healthy controls using qPCR, ELISA, and IHC methods. Results showed decreased MOTS-c mRNA expression in all adrenal tumors compared to controls, while serum MOTS-c protein levels increased in ACA and PCC but not in ACC. The local distribution of MOTS-c protein in adrenal tissue was reduced in all tumors. Notably, MOTS-c protein expression declined with ACC progression (stages III and IV) but was unrelated to patient age or sex. Tumor size and testosterone levels positively correlated with MOTS-c mRNA but negatively with serum MOTS-c protein. Additionally, serum MOTS-c protein correlated positively with glucose, total cholesterol, HDL, LDL, and SHGB levels. These findings suggest disrupted expression of MOTS-c in the spectrum of adrenal diseases, which might be caused by mechanisms involving increased mitochondrial dysfunction and structural changes in the tissue associated with disease progression. This study provides a detailed examination of MOTS-c mRNA and protein in adrenal tumors, indicating the potential role of MDPs in tumor biology and progression.

Adrenocortical carcinoma is a rare malignancy with an annual worldwide incidence of 1–2 cases per 1 million and a 5-year survival rate of <60%. Although adrenocortical carcinoma is rare, such rare cancers account for approximately one third of patients diagnosed with cancer annually. In the past decade, there have been considerable advances in understanding the molecular basis of adrenocortical carcinoma. The genetic events associated with adrenocortical carcinoma in adults are distinct from those of paediatric cases, which are often associated with germline or somatic TP53 mutations and have a better prognosis. In adult primary adrenocortical carcinoma, the main somatic genetic alterations occur in genes that encode proteins involved in the WNT–β-catenin pathway, cell cycle and p53 apoptosis pathway, chromatin remodelling and telomere maintenance pathway, cAMP–protein kinase A (PKA) pathway or DNA transcription and RNA translation pathways. Recently, integrated molecular studies of adrenocortical carcinomas, which have characterized somatic mutations and the methylome as well as gene and microRNA expression profiles, have led to a molecular classification of these tumours that can predict prognosis and have helped to identify new therapeutic targets. In this Review, we summarize these recent translational research advances in adrenocortical carcinoma, which it is hoped could lead to improved patient diagnosis, treatment and outcome.Adrenocortical carcinoma is a rare endocrine cancer with a dismal survival rate and limited therapeutic options. This Review outlines the recent advances that have been made in the understanding of the molecular basis of adrenocortical carcinoma and what this means for the diagnosis and treatment of patients with this cancer type.

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. Adrenocortical carcinomas (ACC) are aggressive and often resistant to therapy. Here, the authors provide a single-nucleus transcriptomic atlas of ACCs and normal adrenal glands, finding ecotypes in steroid and microenvironment cells that are associated with clinical outcomes.

Epigenetic changes are present in all human cancers and are responsible for switching on or off genes, thus controlling tumor cell transcriptome. These changes occur through DNA methylation, histone modifiers and readers, chromatin remodelers, and microRNAs. The histone H3 methyl-transferase EZH2 gene is overexpressed in several cancer types, including adrenocortical carcinoma (ACC), a rare cancer still lacking a targeted therapy. EZH2 inhibitors (EZH2i) have been tested in several clinical trials, but their effectiveness was limited by the toxic effects of the therapeutic doses. We tested several EZH2i on ACC cells, and observed a significant reduction in cell growth only with doses much higher than those required to prevent H3 methylation. We found that all tested EZH2i doses affected lipid metabolism genes, ROS, and glutathione production. Transcript changes correlated with metabolic data, which suggested the effects of EZH2i on ferroptosis. We found that EZH2i dose-dependently increased SLC7A11/glutathione axis and glutathione peroxidase-4 (GPX4), required to counteract lipid peroxidation and ferroptosis. A GPX4 inhibitor synergized with EZH2i, making low doses - which otherwise do not affect cell viability - able to significantly reduce ACC cell growth in vitro and in vivo. Importantly, we found that the anti-ferroptosis defense mechanism induced by EZH2i is a common response for several aggressive tumor phenotypes, uncovering a general co-targetable mechanism that could limit EZH2i effectiveness. Correcting this antioxidant response by ferroptosis inducers may be a new combination therapy that will easily find clinical applications.

Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with a poor prognosis, and its clinical management remains a significant challenge due to the high recurrence rates and limited treatment options. Despite advances in understanding the molecular mechanisms underlying ACC, no reliable biomarkers have been validated for routine clinical use. We analyzed RNA sequencing data from The Cancer Genome Atlas (TCGA) database (n=79) and Genotype Tissue Expression (GTEx) database (n=128) to investigate the expression of VGF in ACC and normal adrenal tissues. Gene expression levels of VGF were quantified and correlated with clinicopathological features and survival outcomes. Statistical methods included Cox proportional hazards models and Kaplan-Meier analysis, while Gene Set Enrichment Analysis (GSEA) was utilized to identify relevant biological pathways associated with VGF expression. Clinical data from 7 ACC patients from YANTAI YUHUANGDING Hospital were also analyzed. The expression of VGF in ACC and normal adrenal gland tissue was further validated through IHC experiments. Our results demonstrate that VGF expression is elevated in ACC tissues compared to normal adrenal tissues and is significantly associated with advanced disease stages, lymph node involvement, metastasis and poor overall survival. VGF levels also correlate with immune cell infiltration, including Th2 cells, T helper cells, and Neutrophils. Importantly, our study establishes VGF as a potential prognostic biomarker for ACC and highlights its role in tumor progression and immune modulation. Additionally, GSEA analysis suggests that VGF is involved in cytokine receptor interaction and the P13K-Akt signaling pathway, possibly relating to tumor immunity. VGF could serve as a valuable marker for patient stratification, monitoring disease progression, and predicting responses to immunotherapies. Future studies should focus on investigating circulating VGF levels as a non-invasive biomarker for ACC to improve clinical management and treatment outcomes.

Adrenocortical carcinoma (ACC) is an aggressive cancer with a poor prognosis. Mitotane, the only FDA-approved treatment for ACC, targets adrenocortical cells and reduces cortisol levels. Although it remains the cornerstone of systemic therapy, its overall impact on long-term outcomes is still a matter of ongoing clinical debate. Drug repurposing is a cost-effective way to identify new therapies, and defactinib, currently in clinical trials as part of combination therapies for various solid tumours, may enhance ACC treatment. We aimed to assess its efficacy in combination with mitotane. We tested the combination of mitotane and defactinib in H295R, SW13, and mitotane-sensitive and -resistant HAC15 cells, using functional assays, transcriptomic profiling, 2D and 3D cultures, bioprinted tissues, and xenografts. We assessed drug interactions with NMR and toxicity in vivo, as mitotane and defactinib have never been previously administered together. Genomic data from 228 human ACC and 158 normal adrenal samples were also analysed. Transcriptomic analysis revealed dysregulation of focal adhesion along with mitotane-related pathways. Focal adhesion kinase (FAK) signalling was enhanced in ACC compared to normal adrenal glands, with PTK2 (encoding FAK) upregulated in 44% of tumour samples due to copy number alterations. High FAK signature scores correlated with worse survival outcomes. FAK inhibition by defactinib, both alone and in combination with mitotane, showed effective anti-tumour activity in vitro. No toxicity or drug—drug interactions were observed in vivo. Combination treatment significantly reduced tumour volume and the number of macrometastases compared to those in the mitotane and control groups, with defactinib-treated tumours showing increased necrosis in xenografts. Defactinib combined with conventionally used mitotane shows promise as a novel combination therapy for ACC and warrants further investigation.