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6. Expression and Prognostic Relevance of PD-1, PD-L1, and CTLA-4 Immune Checkpoints in Adrenocortical Carcinoma.

Author

Landwehr, Laura-Sophie, Altieri, Barbara, Sbiera, Iuliu, Remde, Hanna, Kircher, Stefan, Olabe, Julie, Sbiera, Silviu, Kroiss, Matthias, and Fassnacht, Martin

Subjects
IMMUNE checkpoint proteins, CYTOTOXIC T lymphocyte-associated molecule-4, IMMUNE checkpoint inhibitors, PROGRAMMED cell death 1 receptors, TREATMENT effectiveness
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. [ABSTRACT FROM AUTHOR]

Published
2024
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7. Single‐nucleus and spatial transcriptome reveal adrenal homeostasis in normal and tumoural adrenal glands.

Author

Altieri, Barbara, Secener, A. Kerim, Sai, Somesh, Fischer, Cornelius, Sbiera, Silviu, Arampatzi, Panagiota, Kircher, Stefan, Herterich, Sabine, Landwehr, Laura‐Sophie, Vitcetz, Sarah N., Braeuning, Caroline, Fassnacht, Martin, Ronchi, Cristina L., and Sauer, Sascha

Subjects
ADRENAL cortex, ADRENAL glands, FIBROBLAST growth factors, CELL analysis, CELL populations, WNT genes, ADRENAL tumors
Abstract

The human adrenal gland is a complex endocrine tissue. Studies on adrenal renewal have been limited to animal models or human foetuses. Enhancing our understanding of adult human adrenal homeostasis is crucial for gaining insights into the pathogenesis of adrenal diseases, such as adrenocortical tumours. Here, we present a comprehensive cellular genomics analysis of the adult human normal adrenal gland, combining single‐nuclei RNA sequencing and spatial transcriptome data to reconstruct adrenal gland homeostasis. As expected, we identified primary cells of the various zones of the adrenal cortex and medulla, but we also uncovered additional cell types. They constitute the adrenal microenvironment, including immune cells, mostly composed of a large population of M2 macrophages, and new cell populations, including different subpopulations of vascular‐endothelial cells and cortical‐neuroendocrine cells. Utilizing spatial transcriptome and pseudotime trajectory analysis, we support evidence of the centripetal dynamics of adrenocortical cell maintenance and the essential role played by Wnt/β‐catenin, sonic hedgehog, and fibroblast growth factor pathways in the adult adrenocortical homeostasis. Furthermore, we compared single‐nuclei transcriptional profiles obtained from six healthy adrenal glands and twelve adrenocortical adenomas. This analysis unveiled a notable heterogeneity in cell populations within the adenoma samples. In addition, we identified six distinct adenoma‐specific clusters, each with varying distributions based on steroid profiles and tumour mutational status. Overall, our results provide novel insights into adrenal homeostasis and molecular mechanisms potentially underlying early adrenocortical tumorigenesis and/or autonomous steroid secretion. Our cell atlas represents a powerful resource to investigate other adrenal‐related pathologies. [ABSTRACT FROM AUTHOR]

Published
2024
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9. High Filamin a Expression in Adrenocortical Carcinomas Is Associated with a Favourable Tumour Behaviour: A European Multicentric Study

Author

Catalano, Rosa, primary, Altieri, Barbara, additional, Angelousi, Anna, additional, Arosio, Maura, additional, Bravi, Francesca, additional, Canu, Letizia, additional, Croci, Giorgio A., additional, Detomas, Mario, additional, Esposito, Emanuela, additional, Ferrante, Emanuele, additional, Ferrero, Stefano, additional, Fuss, Carmina T., additional, Kaltsas, Gregory, additional, Kimpel, Otilia, additional, Landwehr, Laura-Sophie, additional, Luconi, Michaela, additional, Morelli, Valentina, additional, Nesi, Gabriella, additional, Nozza, Emma, additional, Sbiera, Silviu, additional, Serban, Andreea L., additional, Ronchi, Cristina L., additional, Mantovani, Giovanna, additional, and Peverelli, Erika, additional

Published
2023
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13. ROR-1 specific CAR-T cells with CRISPR/CAS9 mediated glucocorticoid receptor-knockout exert potent antitumor efficacy in advanced adrenocortical carcinoma

Author

Schauer, Marc Philipp, primary, Altieri, Barbara, additional, Redondo-Frutos, Rodrigo A, additional, Spieler, Peter, additional, Maier, Tanja, additional, Oppelt, Daniel, additional, Kroiss, Matthias, additional, Sbiera, Silviu, additional, Weber, Justus, additional, Fassnacht, Martin, additional, Landwehr, Laura-Sophie, additional, and Hudecek, Michael, additional

Published
2023
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14. WEE1 kinase inhibitor, adavosertib (AZD1775), as a novel potential therapeutic strategy in advanced adrenocortical carcinoma

Author

Tamburello, Mariangela, primary, Sbiera, Silviu, additional, Justus, Weber, additional, Lippert, Juliane, additional, Detomas, Mario, additional, Schauer, Marc Philipp, additional, Urlaub, Hanna, additional, Steinhauer, Sonja, additional, Kimpel, Otilia, additional, Landwehr, Laura-Sophie, additional, Constanze, Hantel, additional, Sigala, Sandra, additional, Ronchi, Cristina, additional, Hudecek, Michael, additional, Katja, Kiseljak-Vassiliades, additional, Fassnacht, Martin, additional, and Altieri, Barbara, additional

Published
2023
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18. CAR-T cell therapy exerts effective antitumor efficacy under immunosuppressive conditions in adrenocortical carcinoma

Author

Philipp, Schauer Marc, primary, Landwehr, Laura-Sophie, additional, Justus, Weber, additional, Altieri, Barbara, additional, Rodrigo, Redundo-Frutos, additional, Tanja, Maier, additional, Daniel, Oppelt, additional, Kroiss, Matthias, additional, Sbiera, Silviu, additional, Michael, Hudecek, additional, and Fassnacht, Martin, additional

Published
2023
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20. PPARG dysregulation as a potential molecular target in adrenal Cushing's syndrome

Author

Vetrivel, Sharmilee, Tamburello, Mariangela, Oßwald, Andrea, Zhang, Ru, Khan, Ali, Jung, Sara, Baker, Jessica E, Rainey, William E, Nowak, Elisabeth, Altieri, Barbara, Detomas, Mario, Watts, Deepika, Williams, Tracy Ann, Wielockx, Ben, Beuschlein, Felix; https://orcid.org/0000-0001-7826-3984, Reincke, Martin, Sbiera, Silviu, Riester, Anna, Vetrivel, Sharmilee, Tamburello, Mariangela, Oßwald, Andrea, Zhang, Ru, Khan, Ali, Jung, Sara, Baker, Jessica E, Rainey, William E, Nowak, Elisabeth, Altieri, Barbara, Detomas, Mario, Watts, Deepika, Williams, Tracy Ann, Wielockx, Ben, Beuschlein, Felix; https://orcid.org/0000-0001-7826-3984, Reincke, Martin, Sbiera, Silviu, and Riester, Anna

Abstract

BACKGROUND We performed a transcriptomic analysis of adrenal signaling pathways in various forms of endogenous Cushing's syndrome (CS) to define areas of dysregulated and druggable targets. METHODOLOGY Next-generation sequencing was performed on adrenal samples of patients with primary bilateral macronodular adrenal hyperplasia (PBMAH, n=10) and control adrenal samples (n=8). The validation groups included cortisol-producing adenoma (CPA, n=9) and samples from patients undergoing bilateral adrenalectomy for Cushing's disease (BADX-CD, n=8). In vivo findings were further characterized using three adrenocortical cell-lines (NCI-H295R, CU-ACC2, MUC1). RESULTS Pathway mapping based on significant expression patterns identified PPARG (peroxisome proliferator-activated receptor gamma) pathway as the top hit. Quantitative PCR (QPCR) confirmed that PPARG (l2fc<-1.5) and related genes - FABP4 (l2fc<-5.5), PLIN1 (l2fc<-4.1) and ADIPOQ (l2fc<-3.3) - were significantly downregulated (p<0.005) in PBMAH. Significant downregulation of PPARG was also found in BADX-CD (l2fc<-1.9, p<0.0001) and CPA (l2fc<-1.4, p<0.0001). In vitro studies demonstrated that the PPARG activator rosiglitazone resulted in decreased cell viability in MUC1 and NCI-H295R (p<0.0001). There was also a significant reduction in the production of aldosterone, cortisol, and cortisone in NCI-H295R and in Dihydrotestosterone (DHT) in MUC1 (p<0.05), respectively. OUTCOME This therapeutic effect was independent of the actions of ACTH, postulating a promising application of PPARG activation in endogenous hypercortisolism.

Published
2023

22. Supplementary Figure Legend from Ribonucleotide Reductase Large Subunit (RRM1) Gene Expression May Predict Efficacy of Adjuvant Mitotane in Adrenocortical Cancer

Author

Volante, Marco, primary, Terzolo, Massimo, primary, Fassnacht, Martin, primary, Rapa, Ida, primary, Germano, Antonina, primary, Sbiera, Silviu, primary, Daffara, Fulvia, primary, Sperone, Paola, primary, Scagliotti, Giorgio, primary, Allolio, Bruno, primary, Papotti, Mauro, primary, and Berruti, Alfredo, primary

Published
2023
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23. Supplementary Tables S1-S2 from β-Catenin Activation Is Associated with Specific Clinical and Pathologic Characteristics and a Poor Outcome in Adrenocortical Carcinoma

Author

Gaujoux, Sébastien, primary, Grabar, Sophie, primary, Fassnacht, Martin, primary, Ragazzon, Bruno, primary, Launay, Pierre, primary, Libé, Rossella, primary, Chokri, Ilham, primary, Audebourg, Anne, primary, Royer, Benedict, primary, Sbiera, Silviu, primary, Vacher-Lavenu, Marie-Cécile, primary, Dousset, Bertrand, primary, Bertagna, Xavier, primary, Allolio, Bruno, primary, Bertherat, Jérôme, primary, and Tissier, Frédérique, primary

Published
2023
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24. Supplementary Figure 1 from Ribonucleotide Reductase Large Subunit (RRM1) Gene Expression May Predict Efficacy of Adjuvant Mitotane in Adrenocortical Cancer

Author

Volante, Marco, primary, Terzolo, Massimo, primary, Fassnacht, Martin, primary, Rapa, Ida, primary, Germano, Antonina, primary, Sbiera, Silviu, primary, Daffara, Fulvia, primary, Sperone, Paola, primary, Scagliotti, Giorgio, primary, Allolio, Bruno, primary, Papotti, Mauro, primary, and Berruti, Alfredo, primary

Published
2023
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26. Steroid profiling using liquid chromatography mass spectrometry during adrenal vein sampling in patients with primary bilateral macronodular adrenocortical hyperplasia

Author

Zhang, Ru, primary, Rubinstein, German, additional, Vetrivel, Sharmilee, additional, Kunz, Sonja, additional, Vogel, Frederick, additional, Bouys, Lucas, additional, Bertherat, Jérôme, additional, Kroiss, Matthias, additional, Deniz, Sinan, additional, Osswald, Andrea, additional, Knösel, Thomas, additional, Bidlingmaier, Martin, additional, Sbiera, Silviu, additional, Reincke, Martin, additional, and Riester, Anna, additional

Published
2022
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27. Delta-like non-canonical Notch ligand 1 (DLK1) - a novel biomarker in adrenocortical carcinoma

Author

Pittaway, James, primary, Mariniello, Katia, additional, Altieri, Barbara, additional, Sbiera, Iuliu, additional, Sbiera, Silviu, additional, Chung, Teng-Teng, additional, Abdel-Azziz, Tarek, additional, DiMarco, Aimee, additional, Palazzo, Fausto, additional, Akker, Scott A., additional, Landwehr, Laura-Sophie, additional, Ronchi, Cristina, additional, Parvanta, Laila, additional, Drake, William, additional, Kroiss, Matthias, additional, Fassnacht, Martin, additional, and Guasti, Leonardo, additional

Published
2022
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30. Cell Atlas at Single-Nuclei Resolution of the Adult Human Adrenal Gland and Adrenocortical Adenomas

Author

Altieri, Barbara, primary, Secener, A. Kerim, additional, Sai, Somesh, additional, Fischer, Cornelius, additional, Sbiera, Silviu, additional, Arampatzi, Panagiota, additional, Herterich, Sabine, additional, Landwehr, Laura-Sophie, additional, Vitcetz, Sarah N., additional, Braeuning, Caroline, additional, Fassnacht, Martin, additional, Ronchi, Cristina L., additional, and Sauer, Sascha, additional

Published
2022
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31. MicroRNAs and Long Non-Coding RNAs in Adrenocortical Carcinoma

Author

Detomas, Mario, primary, Pivonello, Claudia, additional, Pellegrini, Bianca, additional, Landwehr, Laura-Sophie, additional, Sbiera, Silviu, additional, Pivonello, Rosario, additional, Ronchi, Cristina L., additional, Colao, Annamaria, additional, Altieri, Barbara, additional, and De Martino, Maria Cristina, additional

Published
2022
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36. SOAT1: A Suitable Target for Therapy in High-Grade Astrocytic Glioma?

Author

Löhr, Mario, Härtig, Wolfgang, Schulze, Almut, Kroiß, Matthias, Sbiera, Silviu, Lapa, Constantin, Mages, Bianca, Strobel, Sabrina, Hundt, Jennifer Elisabeth, Bohnert, Simone, Kircher, Stefan, Janaki-Raman, Sudha, Monoranu, Camelia-Maria, Löhr, Mario, Härtig, Wolfgang, Schulze, Almut, Kroiß, Matthias, Sbiera, Silviu, Lapa, Constantin, Mages, Bianca, Strobel, Sabrina, Hundt, Jennifer Elisabeth, Bohnert, Simone, Kircher, Stefan, Janaki-Raman, Sudha, and Monoranu, Camelia-Maria

Abstract

Targeting molecular alterations as an effective treatment for isocitrate dehydrogenasewildtype glioblastoma (GBM) patients has not yet been established. Sterol-O-Acyl Transferase 1 (SOAT1), a key enzyme in the conversion of endoplasmic reticulum cholesterol to esters for storage in lipid droplets (LD), serves as a target for the orphan drug mitotane to treat adrenocortical carcinoma. Inhibition of SOAT1 also suppresses GBM growth. Here, we refined SOAT1-expression in GBM and IDH-mutant astrocytoma, CNS WHO grade 4 (HGA), and assessed the distribution of LD in these tumors. Twenty-seven GBM and three HGA specimens were evaluated by multiple GFAP, Iba1, IDH1 R132H, and SOAT1 immunofluorescence labeling as well as Oil Red O staining. To a small extent SOAT1 was expressed by tumor cells in both tumor entities. In contrast, strong expression was observed in glioma-associated macrophages. Triple immunofluorescence labeling revealed, for the first time, evidence for SOAT1 colocalization with Iba1 and IDH1 R132H, respectively. Furthermore, a notable difference in the amount of LD between GBM and HGA was observed. Therefore, SOAT1 suppression might be a therapeutic option to target GBM and HGA growth and invasiveness. In addition, the high expression in cells related to neuroinflammation could be beneficial for a concomitant suppression of protumoral microglia/macrophages.

Published
2022

38. Single-nuclei transcriptome of adult human adrenal glands reveals novel insights into molecular mechanisms intrinsic to adrenocortical tumourigenesis and cortisol secretion

Author

Altieri, Barbara, primary, Secener, Ali Kerim, additional, Sai, Somesh, additional, Fischer, Cornelius, additional, Sbiera, Silviu, additional, Arampatzi, Panagiota, additional, Vitcetz, Sarah, additional, Braeuning, Caroline, additional, Sauer, Sascha, additional, Fassnacht, Martin, additional, and Ronchi, Cristina, additional

Published
2022
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41. Assessment of VAV2 Expression Refines Prognostic Prediction in Adrenocortical Carcinoma

Author

Sbiera, Silviu, Sbiera, Iuliu, Ruggiero, Carmen, Doghman-Bouguerra, Mabrouka, Korpershoek, Esther, de Krijger, Ronald R, Ettaieb, Hester, Haak, Harm, Volante, Marco, Papotti, Mauro, Reimondo, Giuseppe, Terzolo, Massimo, Luconi, Michaela, Nesi, Gabriella, Mannelli, Massimo, Libé, Rossella, Ragazzon, Bruno, Assié, Guillaume, Bertherat, Jérôme, Altieri, Barbara, Fadda, Guido, Rogowski-Lehmann, Natalie, Reincke, Martin, Beuschlein, Felix, Fassnacht, Martin, and Lalli, Enzo

Published
2017

42. SOAT1: A Suitable Target for Therapy in High-Grade Astrocytic Glioma?

Author

Löhr, Mario, primary, Härtig, Wolfgang, additional, Schulze, Almut, additional, Kroiß, Matthias, additional, Sbiera, Silviu, additional, Lapa, Constantin, additional, Mages, Bianca, additional, Strobel, Sabrina, additional, Hundt, Jennifer Elisabeth, additional, Bohnert, Simone, additional, Kircher, Stefan, additional, Janaki-Raman, Sudha, additional, and Monoranu, Camelia-Maria, additional

Published
2022
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43. Role of FGF Receptors and Their Pathways in Adrenocortical Tumors and Possible Therapeutic Implications

Author

Sbiera, Iuliu, Kircher, Stefan, Altieri, Barbara, Lenz, Kerstin, Hantel, Constanze, Fassnacht, Martin, Sbiera, Silviu, Kroiss, Matthias, University of Zurich, Sbiera, Silviu, and Kroiss, Matthias

Subjects
2712 Endocrinology, Diabetes and Metabolism, 10265 Clinic for Endocrinology and Diabetology, 610 Medicine & health, ddc:610
Abstract

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy and treatment of advanced disease is challenging. Clinical trials with multi-tyrosine kinase inhibitors in the past have yielded disappointing results. Here, we investigated fibroblast growth factor (FGF) receptors and their pathways in adrenocortical tumors as potential treatment targets. We performed real-time RT-PCR of 93 FGF pathway related genes in a cohort of 39 fresh frozen benign and malignant adrenocortical, 9 non-adrenal tissues and 4 cell lines. The expression of FGF receptors was validated in 166 formalin-fixed paraffin embedded (FFPE) tissues using RNA in situ hybridization (RNAscope) and correlated with clinical data. In malignant compared to benign adrenal tumors, we found significant differences in the expression of 16/94 FGF receptor pathway related genes. Genes involved in tissue differentiation and metastatic spread through epithelial to mesechymal transition were most strongly altered. The therapeutically targetable FGF receptors 1 and 4 were upregulated 4.6- and 6-fold, respectively, in malignant compared to benign adrenocortical tumors, which was confirmed by RNAscope in FFPE samples. High expression of FGFR1 and 4 was significantly associated with worse patient prognosis in univariate analysis. After multivariate adjustment for the known prognostic factors Ki-67 and ENSAT tumor stage, FGFR1 remained significantly associated with recurrence-free survival (HR=6.10, 95%CI: 1.78 – 20.86, p=0.004) and FGFR4 with overall survival (HR=3.23, 95%CI: 1.52 – 6.88, p=0.002). Collectively, our study supports a role of FGF pathways in malignant adrenocortical tumors. Quantification of FGF receptors may enable a stratification of ACC for the use of FGFR inhibitors in future clinical trials.

Published
2021

45. Identifying New Potential Biomarkers in Adrenocortical Tumors Based on mRNA Expression Data Using Machine Learning

Author

Marquardt, André, Landwehr, Laura-Sophie, Ronchi, Cristina L., Dalmazi, Guido di, Riester, Anna, Kollmannsberger, Philip, Altieri, Barbara, Fassnacht, Martin, Sbiera, Silviu, Marquardt A., Landwehr L.-S., Ronchi C.L., Di Dalmazi G., Riester A., Kollmannsberger P., Altieri B., Fassnacht M., and Sbiera S.

Subjects
machine learning, nervous system, In silico analysi, bioinformatic clustering, adrenocortical carcinoma, in silico analysis, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, biomarker prediction, ddc:610, behavioral disciplines and activities, psychological phenomena and processes, RC254-282, Article
Abstract

Simple Summary Using a visual-based clustering method on the TCGA RNA sequencing data of a large adrenocortical carcinoma (ACC) cohort, we were able to classify these tumors in two distinct clusters largely overlapping with previously identified ones. As previously shown, the identified clusters also correlated with patient survival. Applying the visual clustering method to a second dataset also including benign adrenocortical samples additionally revealed that one of the ACC clusters is more closely located to the benign samples, providing a possible explanation for the better survival of this ACC cluster. Furthermore, the subsequent use of machine learning identified new possible biomarker genes with prognostic potential for this rare disease, that are significantly differentially expressed in the different survival clusters and should be further evaluated. Abstract Adrenocortical carcinoma (ACC) is a rare disease, associated with poor survival. Several “multiple-omics” studies characterizing ACC on a molecular level identified two different clusters correlating with patient survival (C1A and C1B). We here used the publicly available transcriptome data from the TCGA-ACC dataset (n = 79), applying machine learning (ML) methods to classify the ACC based on expression pattern in an unbiased manner. UMAP (uniform manifold approximation and projection)-based clustering resulted in two distinct groups, ACC-UMAP1 and ACC-UMAP2, that largely overlap with clusters C1B and C1A, respectively. However, subsequent use of random-forest-based learning revealed a set of new possible marker genes showing significant differential expression in the described clusters (e.g., SOAT1, EIF2A1). For validation purposes, we used a secondary dataset based on a previous study from our group, consisting of 4 normal adrenal glands and 52 benign and 7 malignant tumor samples. The results largely confirmed those obtained for the TCGA-ACC cohort. In addition, the ENSAT dataset showed a correlation between benign adrenocortical tumors and the good prognosis ACC cluster ACC-UMAP1/C1B. In conclusion, the use of ML approaches re-identified and redefined known prognostic ACC subgroups. On the other hand, the subsequent use of random-forest-based learning identified new possible prognostic marker genes for ACC.

Published
2021

46. Mitotane Inhibits Sterol-O-Acyl Transferase 1 Triggering Lipid-Mediated Endoplasmic Reticulum Stress and Apoptosis in Adrenocortical Carcinoma Cells

Author

Sbiera, Silviu, Leich, Ellen, Liebisch, Gerhard, Sbiera, Iuliu, Schirbel, Andreas, Wiemer, Laura, Matysik, Silke, Eckhardt, Carolin, Gardill, Felix, Gehl, Annemarie, Kendl, Sabine, Weigand, Isabel, Bala, Margarita, Ronchi, Cristina L., Deutschbein, Timo, Schmitz, Gerd, Rosenwald, Andreas, Allolio, Bruno, Fassnacht, Martin, and Kroiss, Matthias

Published
2015

48. Epithelial and Mesenchymal Markers in Adrenocortical Tissues: How Mesenchymal Are Adrenocortical Tissues?

Author

Sbiera, Iuliu, Kircher, Stefan, Altieri, Barbara, Fassnacht, Martin, Kroiss, Matthias, and Sbiera, Silviu

Subjects
adrenocortical tissues, embryonic structures, EMT, mesenchymal markers, ddc:610, recurrence-free survival, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, lcsh:RC254-282, Article, epithelial markers
Abstract

Simple Summary Recent studies have hinted to an involvement of epithelial to mesenchymal transition, a mechanism often associated with metastasis in epithelial cancers, in adrenocortical carcinoma. We assessed, in a large number of normal, benign and malignant adrenocortical tissues, the expression of canonical epithelial and mesenchymal markers and compared it with their expression in typical epithelial and mesenchymal tissues. Surprisingly, both normal and neoplastic adrenocortical tissues lacked expression of epithelial markers but strongly expressed mesenchymal markers, suggesting a higher similarity of adrenocortical tissues to mesenchymal compared to epithelial tissues, reminiscent of the adrenocortical origin from the intermediate mesoderm. Despite their ubiquitous expression in all adrenocortical tissues, mesenchymal markers had a variable expression in ACC, associating either directly or inversely with different clinical markers of tumor aggressiveness. Our data are an important step in better understanding the adrenocortical tissues in general and adrenocortical tumorigenesis in particular, and could be exploited therapeutically in the future. Abstract A clinically relevant proportion of adrenocortical carcinoma (ACC) cases shows a tendency to metastatic spread. The objective was to determine whether the epithelial to mesenchymal transition (EMT), a mechanism associated with metastasizing in several epithelial cancers, might play a crucial role in ACC. 138 ACC, 29 adrenocortical adenomas (ACA), three normal adrenal glands (NAG), and control tissue samples were assessed for the expression of epithelial (E-cadherin and EpCAM) and mesenchymal (N-cadherin, SLUG and SNAIL) markers by immunohistochemistry. Using real-time RT-PCR we quantified the alternative isoform splicing of FGFR 2 and 3, another known indicator of EMT. We also assessed the impact of these markers on clinical outcome. Results show that both normal and neoplastic adrenocortical tissues lacked expression of epithelial markers but strongly expressed mesenchymal markers N-cadherin and SLUG. FGFR isoform splicing confirmed higher similarity of adrenocortical tissues to mesenchymal compared to epithelial tissues. In ACC, higher SLUG expression was associated with clinical markers indicating aggressiveness, while N-cadherin expression inversely associated with these markers. In conclusion, we could not find any indication of EMT as all adrenocortical tissues lacked expression of epithelial markers and exhibited closer similarity to mesenchymal tissues. However, while N-cadherin might play a positive role in tissue structure upkeep, SLUG seems to be associated with a more aggressive phenotype.

Published
2021

50. Steroid profiling using liquid chromatography mass spectrometry during adrenal vein sampling in patients with primary bilateral massive adrenal hyperplasia

Author

Zhang, Ru, primary, Rubinstein, German, additional, Vetrivel, Sharmilee, additional, Vogel, Frederick, additional, Kroiss, Matthias, additional, Deniz, Sinan, additional, Osswald, Andrea, additional, Knosel, Thomas, additional, Kunz, Sonja, additional, Bidlingmaier, Martin, additional, Sbiera, Silviu, additional, Reincke, Martin, additional, and Riester, Anna, additional

Published
2021
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