Adrenal gland – crossroads of stress response – epigenetic, transcriptional, and metabolic analyses

Principal Investigators

Project Description

Within the HPA axis there is a fine regulation of the stress response in the adrenal gland at multiple levels, exemplified by its complex genetic, epigenetic, transcriptomic, and metabolic regulation. This is crucial for the homeostatic upkeep, and even small disruptions may have serious influences as revealed by the specific adrenal phenotypes associated with hypercortisolism. However, knowledge of the players involved in this homeostatic fine regulation is still very limited. We hypothesise that secondary modifications at DNA and RNA level are paramount for this control; therefore we aim to define the contribution of epigenetic and epitranscriptomic modifications as well as of metabolome changes in situ on steroid synthesis and secretion in a unique collection of adrenal tumours characterized by stress-hormone cortisol overproduction.

Aims

(I) Investigate epigenetic and epitranscriptomic modifications in adrenal tumour tissues leading to hypercortisolism

(II) Verify consequences of epigenetic and epitranscriptomic modifications on steroid hypersecretion in 3 D cell cultures

(III) Study the impact of epigenetic and epitranscriptomic modifications on the adrenal metabolic microenviroment using MALDI-MSI

(IV) Establish functional consequences of epigenetic, transcriptional and metabolic regulations on plasma and urine steroid secretion

Publications

1. Oreglia M, Sbiera S, Fassnacht M, Guyon L, Denis J, Cristante J, Chabre O, Cherradi N. Early Postoperative Circulating miR-483-5p Is a Prognosis Marker for Adrenocortical Cancer. Cancers (Basel). 2020;12. pii: E724.
2. Prognostic Relevance of Steroid Sulfation in Adrenocortical Carcinoma Revealed by Molecular Phenotyping Using High-Resolution Mass Spectrometry Imaging. Clin Chem. 2019;65:1276-1286.
3. Chortis V, …(+6)…, Riester A, …(+50)…, Fassnacht M, Beuschlein F, …(+6)…, Arlt W. Urine steroid metabolomics for the differential diagnosis of adrenal incidentalomas: A prospective test validation study. Lancet DE 2020. doi:10.1016/S2213-8587(20)30218-7
4. Gilligan LC, Taylor AE, Ronchi CL, O’Reilly MW, Schreiner J, Asia M, Riester A, …(+12)…, Beuschlein F, Fassnacht M, Deeks JJ, Biehl M, Arlt W. Urine Steroid Metabolomics as a Novel Tool for Detection of Recurrent Adrenocortical Carcinoma. J Clin Endocrinol Metab. 2020;105
5. , Perez-Rivas LG, Taranets L, Weigand I, Flitsch J, …(+11)…, Reincke M, Strom TM, Popov N, Theodoropoulou M, Fassnacht M. Driver mutations in USP8 wild-type Cushing’s disease. Neuro Oncol. 2019;21:1273-1283.
6. RNA-Sequencing and Somatic Mutation Status of Adrenocortical Tumors: Novel Pathogenetic Insights. J Clin Endocrinol Metab (2020)