Endocrinology

About the research

Thyroid tumour research comprises a large programme (McCabe) aimed at improving radioiodine treatment of aggressive thyroid cancers via new understanding of sodium iodide symporter (NIS) trafficking. Via novel high-throughput drug screening, several drugs have been identified that increase NIS function at the plasma membrane, now systematically appraised in thyroid and breast cancer models. Recent work has identified unique gene and miRNA changes in early thyroid cancer recurrence, now evaluated by Nanopore DNA sequencing of fine needle aspirants for rapid detection of patient driver mutations. Vicki Smith investigates the roles of the understudied proto-oncogenes PBF and PTTG in thyroid and breast cancer, focussing on cellular signalling pathways and their disruption in neoplasia. Her current research examines the interplay between signal transduction and actin dynamics that drives tumour cell motility and invasion.

Publications

Targeting novel sodium iodide symporter interactors ADP-ribosylation factor 4 (ARF4) and valosin-containing protein (VCP) enhances radioiodine uptake. Fletcher A, Read ML, Thornton CEM, Larner DP, Poole VL, Brookes K, Nieto HR, Alshahrani M, Thompson RJ, Lavery GG, Landa I, Fagin JA, Campbell MJ, Boelaert K, Turnell AS, Smith VE, McCabe CJ. Cancer Research 2020 80(1):102-115

PTTG and PBF Functionally Interact with p53 and Predict Overall Survival in Head and Neck Cancer. Read ML, Modasia B, Fletcher A, Thompson RJ, Brookes K, Rae PC, Nieto HR, Poole VL, Roberts S, Campbell MJ, Boelaert K, Turnell AS, Smith VE, Mehanna H, McCabe CJ. Cancer Research 2018 Oct 15;78(20):5863-5876.

About the research

Adrenal tumour research focusses on both common conditions (adrenal incidentaloma – 5% of the population with metabolic disease burden, Conn’s syndrome affecting 10% of hypertensives) and rare but devastating adrenocortical carcinoma (ACC; 5-year survival rate 30-40%). Through the European Network for the Study of Adrenal Tumours (ENSAT) we have access to a global network of other internationally leading teams. Combining mass spectrometry-based urine multi-steroid profiling and machine learning methods for data analysis, we have used this novel urine steroid metabolomics approach to uncover prevalent cortisol excess in mineralocorticoid hypertension and to develop a biomarker tool for the non-invasive diagnosis of ACC, recently validated in an ENSAT multi-centre trial led by Arlt with Chortis (EURINE-ACT), now in the process of roll-out to clinical practice.

Ronchi has developed novel applications of targeted molecular analyses including a liquid biopsy approach for rapid detection of ACC recurrence and also uses novel cell and tissue-based models for the identification of novel therapeutic targets for ACC treatment, and collaborating with Calebiro to investigate GPCR alterations in cortisol excess. Elhassan and Calebiro are collaborating in studying receptor signalling in adrenocortical tumours utilising state-of-the-art methodology, such as live-cell imaging, with the aim to understand tumour pathogenesis. Additional work targets the metabolic impact of mild autonomous cortisol excess (MACE) in adrenal incidentalomas (Prete, Arlt, Manolopoulos) and the significance of mineralocorticoid excess in hypertension (Lang, Prete, Arlt).

Publications

Urine steroid metabolomics as a novel tool for detection of recurrent adrenocortical carcinoma. Chortis V, Bancos I, Nijman T, Gilligan LC, Taylor AE, Ronchi CL, O'Reilly MW, Schreiner J, Asia M, Riester A, Perotti P, Libé R, Quinkler M, Canu L, Paiva I, Bugalho MJ, Kastelan D, Dennedy MC, Sherlock M, Ambroziak U, Vassiliadi D, Bertherat J, Beuschlein F, Fassnacht M, Deeks JJ, Biehl M, Arlt W. J Clin Endocrinol Metab. 2019 Oct 29. [Epub ahead of print]

Natural History of Adrenal Incidentalomas With and Without Mild Autonomous Cortisol Excess: A Systematic Review and Meta-analysis. Elhassan YS, Alahdab F, Prete A, Delivanis DA, Khanna A, Prokop L, Murad MH, O'Reilly MW, Arlt W, Bancos I. Ann Intern Med. 2019 Jun 25. [Epub ahead of print]

About the research

Our research into endocrine-related cancers spans the understanding of basic steroidal metabolism to drug discovery and translational clinical medicine. By using our Steroid Metabolome Analysis Core, we are investigating how mapping steroid output from endocrine-related cancers can inform new diagnostic tests and drug discovery opportunities (Arlt, Jeevan Foster). Studies have also highlighted oestrogen metabolism through 17β-hydroxysteroid dehydrogenases as a potential driver of colorectal cancer and thus opening up this malignancy for novel approaches for new treatment (Foster).

Publications

Assessment of the Safety of Glucocorticoid Regimens in Combination With Abiraterone Acetate: A Randomized, Open-Label Phase 2 Study. Attard G, Merseburger AS, Arlt W, Sternberg CN, Feyerabend S, Berruti A, Joniau S, Géczi L, Lefresne F, Lahaye M, Shelby FN, Pissart G, Chua S, Jones RJ, Tombal B. JAMA Oncol. 2019 Jun 27. [Epub ahead of print]

Quinazolinone-Based Anticancer Agents: Synthesis, Antiproliferative SAR, Antitubulin Activity, and Tubulin Co-crystal Structure. Dohle W, Jourdan FL, Menchon G, Prota AE, Foster PA, Mannion P, Hamel E, Thomas MP, Kasprzyk PG, Ferrandis E, Steinmetz MO, Leese MP, Potter BVL. J Med Chem. 2018 Feb 8;61(3):1031-1044

About the research

Research into disorders of steroidogenesis (Arlt, Idkowiak, Mueller) draws on our unique capability for integrated steroid metabolome analysis (Taylor, Zavala) and focusses on the physiology of adrenal and gonadal development as well as clinical and translational aspects of primary adrenal insufficiency, congenital adrenal hyperplasia and other inborn disorders of steroidogenesis.

Publications

Alternative pathway androgen biosynthesis and human fetal female virilization. Reisch N, Taylor AE, Nogueira EF, Asby DJ, Dhir V, Berry A, Krone N, Auchus RJ, Shackleton CHL, Hanley NA, Arlt W.  Proc Natl Acad Sci U S A. 2019 Oct 29;116(44):22294-22299.

Human DHEA sulfation requires direct interaction between PAPS synthase 2 and DHEA sulfotransferase SULT2A1. Mueller JW, Idkowiak J, Gesteira TF, Vallet C, Hardman R, van den Boom J, Dhir V, Knauer SK, Rosta E, Arlt W. J Biol Chem. 2018 Jun 22;293(25):9724-9735.

About the research

One particular strength is our ability to develop innovative microscopy methodologies (Calebiro), in combination with new biosensors, to monitor receptor signalling directly in living cells and tissues with unprecedented spatiotemporal resolution. This is combined with novel mathematical and computational approaches to extract quantitative information from complex imaging data and model receptor signalling at both molecular and cellular level.

Publications

Siddig S, Aufmkolk S, Doose S, Jobin ML, Werner C, Sauer M, Calebiro D.Sci Adv. 2020 Super-resolution imaging reveals the nanoscale organization of metabotropic glutamate receptors at presynaptic active zones. Apr 15;6(16):eaay7193. doi: 10.1126/sciadv.aay7193. eCollection 2020 Apr

Sungkaworn T, Jobin ML, Burnecki K, Weron A, Lohse MJ, Calebiro D. Single-molecule imaging reveals receptor-G protein interactions at cell surface hot spots. Nature. 2017 Oct 26;550(7677):543-547. doi: 10.1038/nature24264.

Bathon K, Weigand I, Vanselow JT, Ronchi CL, Sbiera S, Schlosser A, Fassnacht M, Calebiro D. Alterations in Protein Kinase A Substrate Specificity as a Potential Cause of Cushing Syndrome. Endocrinology. 2019 Feb 1;160(2):447-459. doi: 10.1210/en.2018-00775.