Na Sun1, Thomas Kunzke1, Silviu Sbiera2, Stefan Kircher3, Annette Feuchtinger4, Michaela Aichler4, Sabine Herterich5, Cristina L Ronchi2,6, Isabel Weigand2, Nicolas Schlegel7,8, Jens Waldmann9, Maria Candida Villares Fragoso10, Timothy G Whitsett11, Anthony J Gill12, Martin Fassnacht2,5,8, Axel Walch4, Matthias Kroiss13,5,8. 1. Research Unit Analytical Pathology, German Research Center for Environmental Health, Helmholtz Zentrum München, Neuherberg, Germany; Kroiss_M@ukw.de. 2. Department of Internal Medicine, Division of Endocrinology and Diabetology, University Hospital Würzburg, Würzburg, Germany. 3. Institute of Pathology, University of Würzburg, Würzburg, Germany. 4. Research Unit Analytical Pathology, German Research Center for Environmental Health, Helmholtz Zentrum München, Neuherberg, Germany. 5. Central Laboratory, University Hospital Würzburg, Würzburg, Germany. 6. Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK. 7. Department of General, Visceral, Vascular, and Paediatric Surgery, University Hospital Würzburg, Würzburg, Germany. 8. Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany. 9. MIVENDO Klinik, Hamburg, Germany. 10. University of Sao Paolo, São Paulo, Brazil. 11. Translational Genomics Research Institute (TGen), Phoenix, AZ. 12. Royal North Shore Hospital and The University of Sydney, Sydney, Australia. 13. Department of Internal Medicine, Division of Endocrinology and Diabetology, University Hospital Würzburg, Würzburg, Germany; Kroiss_M@ukw.de.
Abstract
BACKGROUND: Adrenocortical carcinoma (ACC) is a rare tumor with variable prognosis even within the same tumor stage. Cancer-related sex hormones and their sulfated metabolites in body fluids can be used as tumor markers. The role of steroid sulfation in ACC has not yet been studied. MALDI mass spectrometry imaging (MALDI-MSI) is a novel tool for tissue-based chemical phenotyping. METHODS: We performed phenotyping of formalin-fixed, paraffin-embedded tissue samples from 72 ACC by MALDI-MSI at a metabolomics level. RESULTS: Tumoral steroid hormone metabolites-estradiol sulfate [hazard ratio (HR) 0.26; 95% CI, 0.10-0.69; P = 0.005] and estrone 3-sulfate (HR 0.22; 95% CI, 0.07-0.63; P = 0.003)-were significantly associated with prognosis in Kaplan-Meier analyses and after multivariable adjustment for age, tumor stage, and sex (HR 0.29; 95% CI, 0.11-0.79; P = 0.015 and HR 0.30; 95% CI, 0.10-0.91; P = 0.033, respectively). Expression of sulfotransferase SULT2A1 was associated with prognosis to a similar extent and was validated to be a prognostic factor in two published data sets. We discovered the presence of estradiol-17β 3,17-disulfate (E2S2) in a subset of tumors with particularly poor overall survival. Electron microscopy revealed novel membrane-delimited organelles in only these tumors. By applying cluster analyses of metabolomic data, 3 sulfation-related phenotypes exhibited specific metabolic features unrelated to steroid metabolism. CONCLUSIONS: MALDI-MSI provides novel insights into the pathophysiology of ACC. Steroid hormone sulfation may be used for prognostication and treatment stratification. Sulfation-related metabolic reprogramming may be of relevance also in conditions beyond the rare ACC and can be directly investigated by the use of MALDI-MSI.
BACKGROUND:Adrenocortical carcinoma (ACC) is a rare tumor with variable prognosis even within the same tumor stage. Cancer-related sex hormones and their sulfated metabolites in body fluids can be used as tumor markers. The role of steroid sulfation in ACC has not yet been studied. MALDI mass spectrometry imaging (MALDI-MSI) is a novel tool for tissue-based chemical phenotyping. METHODS: We performed phenotyping of formalin-fixed, paraffin-embedded tissue samples from 72 ACC by MALDI-MSI at a metabolomics level. RESULTS: Tumoral steroid hormone metabolites-estradiol sulfate [hazard ratio (HR) 0.26; 95% CI, 0.10-0.69; P = 0.005] and estrone 3-sulfate (HR 0.22; 95% CI, 0.07-0.63; P = 0.003)-were significantly associated with prognosis in Kaplan-Meier analyses and after multivariable adjustment for age, tumor stage, and sex (HR 0.29; 95% CI, 0.11-0.79; P = 0.015 and HR 0.30; 95% CI, 0.10-0.91; P = 0.033, respectively). Expression of sulfotransferase SULT2A1 was associated with prognosis to a similar extent and was validated to be a prognostic factor in two published data sets. We discovered the presence of estradiol-17β 3,17-disulfate (E2S2) in a subset of tumors with particularly poor overall survival. Electron microscopy revealed novel membrane-delimited organelles in only these tumors. By applying cluster analyses of metabolomic data, 3 sulfation-related phenotypes exhibited specific metabolic features unrelated to steroid metabolism. CONCLUSIONS: MALDI-MSI provides novel insights into the pathophysiology of ACC. Steroid hormone sulfation may be used for prognostication and treatment stratification. Sulfation-related metabolic reprogramming may be of relevance also in conditions beyond the rare ACC and can be directly investigated by the use of MALDI-MSI.
Authors: Jian Shen; Na Sun; Philipp Zens; Thomas Kunzke; Achim Buck; Verena M Prade; Jun Wang; Qian Wang; Ronggui Hu; Annette Feuchtinger; Sabina Berezowska; Axel Walch Journal: Cancer Commun (Lond) Date: 2022-05-20
Authors: Tanja Paul; Stephan Ledderose; Harald Bartsch; Na Sun; Sarah Soliman; Bruno Märkl; Viktoria Ruf; Jochen Herms; Marcel Stern; Oliver T Keppler; Claire Delbridge; Susanna Müller; Guido Piontek; Yuki Schneider Kimoto; Franziska Schreiber; Tracy Ann Williams; Jens Neumann; Thomas Knösel; Heiko Schulz; Ria Spallek; Matthias Graw; Thomas Kirchner; Axel Walch; Martina Rudelius Journal: Nat Commun Date: 2022-03-24 Impact factor: 17.694