Project B17
Signalling network aberrations in corticotroph tumorigenesis and hypercortisolism
The primary cause of endogenous hypercortisolism is excessive adrenocorticotropic hormone (ACTH) production from corticotroph tumours (Cushing’s disease). Resistance to negative glucocorticoid feedback from the adrenals is central in the pathophysiology of Cushing’s disease. At the same time, hypercortisolism affects peripheral tissues, with impaired metabolism being one of the most prominent and hard to manage comorbidities. During the first funding period we consolidated the mutational hotspot in the gene encoding for the ubiquitin specific protease 8 (USP8) and discovered a new mutational hotspot in another deubiquitinase encoding gene, USP48. Mutations in these two genes are found in more than half cases of corticotroph tumours, but no other driver mutations were identified. In parallel, we found that mutant USP8 forms directly affect glucocorticoid receptor action and response to the glucocorticoid feedback, thereby linking corticotroph tumour genetics with a fundamental aspect of Cushing’s disease pathophysiology. Finally, we identified potential novel regulators of ACTH synthesis that could translate to novel treatments. We hypothesise that in the absence of additional driver mutations, the isolated genetic defects triggering these monoclonal neoplasms converge on common signalling pathways that favour aberrant tumour growth and ACTH secretion. Our specific aims are threefold: (i) discover deregulated signalling networks in corticotroph tumours, (ii) define prognostic targets for the management of Cushing’s disease, and (iii) elucidate signalling markers of glucocorticoid sensitivity. To this end, we will analyse transcriptomic and proteomic data and validate hits in in vitro models of Cushing’s disease and patient cohorts. In parallel, we will investigate mechanisms that modulate glucocorticoid signalling on metabolically relevant systems. The intent of our collaborative effort is to discover signalling network aberrations that drive corticotroph tumour progression and the pathology of endogenous hypercortisolism; from this, we will identify novel therapeutic targets and biomarkers.
Aims
(I) Define signalling networks in corticotroph tumorigenesis
(II) Discover targets and create models for the precision management of Cushing’s disease
(III) Elucidate signalling markers of glucocorticoid sensitivity
| Principal Investigators | Institution |
| Prof. Dr. rer. nat. Marily Theodoropoulou | LMU |
| Prof. Dr. med. Martin Reincke | LMU |
