Project B17

Here is supposed to be a picture of the Project B17 of the CRCTRR 205
Marily Theodoropoulou and Martin Reincke

Prof. Dr. med. Martin Reincke
Department Director, Professor of Internal
Medizinische Klinik und Pliklinik IV
Klinikum der Ludwig-Maximilians-Universität Munich

Prof. Dr. rer. nat. Marily Theodoropoulou
W2 Professor of Neuroendocrinology
Medical Clinic and Policlinic IV, Ludwig-Maximilians-Universität Munich

Signalling network aberrations in corticotroph tumorigenesis and hypercortisolism
(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

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.

Xiao Chen (2019-2021) candidate
Title: Studies on the role of integrins on corticotroph tumorigenesis
Julia Simon (2020-2022) Dr.hum.biol. candidate
Title: Studies on molecular mechanisms conferring aggressive behaviour to pituitary neoplasms
Sicheng Tang (2018-2022) candidate
Title: The USP8 system as pathogenic and therapeutic target in Cushing’s disease
Mina Mazari (2021-2022) Candidate
Title: Chronotype in patients with Cushing’s syndrome
Michel Pilot (2021-2022) candidate
Title: Identification and classification of human pituitary tumors using Raman spectroscopy

2020 – European Society of Endocrinology Young Investigator Award (to Adriana Albani)
2019 – German Society of Endocrinology “Schöller‐Junkmann‐Preis” (to Luis Gustavo Perez-Rivas jointly with Isabel Weigand)
2019 – Munich Excellence Training Initiative for Physician Scientists Award to Adriana Albani

Vogel F, Braun L, Rubinstein G, Zopp S, Benedix S, Schneider H, Ritzel K, Schilbach K, Schmidmaier R, Beuschlein F, Bidlingmaier M, Reincke M. Patients with low IGF-I after curative surgery for Cushing’s syndrome have an adverse long-term outcome of hypercortisolism-induced myopathy. Eur J Endocrinol. 2021;184(6):813-821.

Vetrivel S, Zhang R, Engel M, Altieri B, Braun L, Osswald A, Bidlingmaier M, Fassnacht M, Beuschlein F, Reincke M, Chen A, Sbiera S, Riester A. Circulating microRNA Expression in Cushing’s Syndrome. Front Endocrinol (Lausanne). 2021;12:620012.

Lopez JP, Brivio E, Santambrogio A, De Donno C, Kos A, Peters M, Rost N, Czamara D, Brückl TM, Roeh S, Pöhlmann ML, Engelhardt C, Ressle A, Stoffel R, Tontsch A, Villamizar JM, Reincke M, Riester A, Sbiera S, Fassnacht M, Mayberg HS, Craighead WE, Dunlop BW, Nemeroff CB, Schmidt MV, Binder EB, Theis FJ, Beuschlein F, Andoniadou CL, Chen A. Single-cell molecular profiling of all three components of the HPA axis reveals adrenal ABCB1 as a regulator of stress adaptation. Sci Adv. 2021;7(5):eabe4497. doi: 10.1126/sciadv.abe4497.

Reincke M, Theodoropoulou M. Genomics in Cushing’s Disease: The Dawn of a New Era. J Clin Endocrinol Metab. 2021;106(6):e2455-e2456.
Reincke M, Albani A, Assie G, Bancos I, Brue T, Buchfelder M, Chabre O, Ceccato F, Daniele A, Detomas M, Di Dalmazi G, Elenkova A, Findling J, Grossman AB, Gomez-Sanchez CE, Heaney AP, Honegger J, Karavitaki N, Lacroix A, Laws ER, Losa M, Murakami M, Newell-Price J, Pecori Giraldi F, Pérez-Rivas LG, Pivonello R, Rainey WE, Sbiera S, Schopohl J, Stratakis CA, Theodoropoulou M, van Rossum EFC, Valassi E, Zacharieva S, Rubinstein G, Ritzel K. Corticotroph tumor progression after bilateral adrenalectomy (Nelson’s syndrome): systematic review and expert consensus recommendations. Eur J Endocrinol. 2021;184(3):P1-P16.

Albani A, Theodoropoulou M. Persistent Cushing’s Disease after Transsphenoidal Surgery: Challenges and Solutions. Exp Clin Endocrinol Diabetes. 2021;129(3):208-215.

Watts D, Stein J, Meneses A, Bechmann N, Neuwirth A, Kaden D, Krüger A, Sinha A, Ismini Alexaki V, Perez-Rivas LG, Kircher S, Martinez A, Theodoropoulou M, Eisenhofer G, Peitzsch M, El-Armouche A, Chavakis T, Wielockx B. HIF1α is a direct regulator of steroidogenesis in the adrenal gland. Cellular and Molecular Life Sciences. Cell Mol Life Sci. 2021;78(7):3577-3590.

Vogel F, Braun LT, Rubinstein G, Zopp S, Künzel H, Strasding F, Albani A, Riester A, Schmidmaier R, Bidlingmaier M, Quinkler M, Deutschbein T, Beuschlein F, Reincke M. Persisting Muscle Dysfunction in Cushing’s Syndrome Despite Biochemical Remission. J Clin Endocrinol Metab. 2020;105(12):e4490-8.

Albani A, Theodoropoulou M. Persistent Cushing’s Disease after Transsphenoidal Surgery: Challenges and Solutions. Exp Clin Endocrinol Diabetes. 2020. (doi: 10.1055/a-1220-6056).

Sbiera S, Perez-Rivas LG, Taranets L, Weigand I, Flitsch J, Graf E, Monoranu CM, Saeger W, Hagel C, Honegger J, Assie G, Hermus AR, Stalla GK, Herterich S, Ronchi CL, Deutschbein T, Reincke M, Strom TM, Popov N, Theodoropoulou M*, Fassnacht M*. Driver mutations in USP8 wild type Cushing’s disease. Neuro Oncol. 2019;21(10):1273-1283.

Albani A, Berr CM, Beuschlein F, Treitl M, Hallfeldt K, Honegger J, Schnauder G, Reincke M. A pitfall of bilateral inferior petrosal sinus sampling in cyclic Cushing’s syndrome. BMC Endocr Disord. 2019;19(1): 105.

Theodoropoulou M*, Reincke M. Tumor-directed therapeutic targets in Cushing disease. J Clin Endocrinol Metab. 2019;104(3):925-933.  (Invited Review)

Rubinstein G, Osswald A, Zopp S, Ritzel K, Theodoropoulou M, Beuschlein F, Reincke M. Therapeutic options after surgical failure in Cushing’s disease: A critical review. Best Pract Res Clin Endocrinol Metab. 2019;33(2):101270.

Ciato D, Li R, Monteserin Garcia JL, Papst L, D’Annunzio S, Hristov M, Tichomirowa MA, Belaya Z, Rozhinskaya L, Buchfelder M, Theodoropoulou M, Paez-Pereda M, Stalla GK. Inhibition of HSF1 enhances repressive molecular mechanisms on POMC promoter. Neuroendocrinology. 2019;109(4):362-373.

Xekouki P, Lodge EJ, Matschke J, Santambrogio A, Apps JR, Sharif A, Jacques TS, Aylwin S, Prevot V, Li R, Flitsch J, Bornstein SR, Theodoropoulou M*, Andoniadou CL*. Non-secreting pituitary tumours characterised by enhanced expression of YAP/TAZ. Endocr Relat Cancer. 2019;26(1):215-225.

Albani A, Theodoropoulou M, Reincke M. Genetics of Cushing’s disease. Clin Endocrinol (Oxf). 2018;88:3-12.

Albani A, Pérez-Rivas LG, Dimopoulou C, Zopp S, Colón-Bolea P, Roeber S, Honegger J, Flitsch J, Rachinger W, Buchfelder M, Stalla GK, Herms J, Reincke M, Theodoropoulou M*. The USP8 mutational status may predict long-term remission in patients with Cushing’s disease. Clin Endocrinol. 2018;88(1):3-12

Albani A, Perez-Rivas LG, Reincke M, Theodoropoulou M. Pathogenesis of Cushing disease: an update on the genetics of corticotrophinomas. Endocr Pract. 2018;24(10):907-914.

Perez-Rivas LG*, Theodoropoulou M*#, Puar TH, Fazel J, Stieg MR, Ferraù F, Assié G, Gadelha MR, Deutschbein T, Fragoso MC, Kusters B, Saeger W, Honegger J, Buchfelder M, Korbonits M, Bertherat J, Stalla GK, Hermus AR, Beuschlein F, Reincke M. Somatic USP8 mutations are frequent events in corticotroph tumor progression causing Nelson’s tumor. Eur J Endocrinol. 2018; 178:59-65.