Project ID CM-HD2024_12

ThemeCM-HD

Co Supervisor 1A Faculty of Dentistry, Oral & Craniofacial Sciences, Centre for Craniofacial & Regenerative BiologyWebsite

Co Supervisor 1B Guy's & St. Thomas' Hospital, EndocrinologyWebsite

Signalling pathways regulating homeostasis and tumour formation in the adrenal medulla

Definitive evidence for the presence or absence of an adrenomedullary stem cell has been enigmatic to date, but we have recently identified the presence of a bona fide stem cell population in this organ. Renewal of the catecholamine-secreting chromaffin cell population of the adrenal medulla is necessary for physiological homeostasis throughout life, but the signals controlling the cell fate decisions of adrenomedullary stem cells as well as their descendant chromaffin cells are not known. Using genetic approaches in mouse, human adrenomedullary stem cell culture and single cell approaches, this project aims to discern the signalling mechanisms that govern cell fate decisions in this organ, with an emphasis on stem cell regulation. Our recent research on the pituitary gland has revealed that stem cells of this endocrine organ act as signalling hubs, controlling the cell fate decisions of their neighbouring cells through paracrine secretion. The project will explore if this type of regulation also applies to adrenomedullary stem cells. Finally, the project will determine if the critical mechanisms identified are perturbed in the tumours pheochromocytoma and paraganglioma, and if they may underlie the aetiology and pathogenesis of the initial steps of tumour formation. This knowledge will have the potential to open up new treatment avenues.

Main aims:
(i) Dissect the signalling mechanisms that control homeostasis in the adrenal medulla.
(ii) Determine if the non-classical, paracrine contribution of stem cells is important for the regulation of cell fate decisions in the adrenal medulla.
(iii) Identify new signalling mechanisms involved adrenomedullary tumour formation and perturb these in vitro and in vivo.

Techniques:
Molecular biology, mouse genetics and husbandry, histology, immunofluorescence, mRNA in situ hybridisation, dissections primary tissue culture, computational analysis using R.

Representative Publications

Russell JP, Lim X, Santambrogio A, Yianni V, Kemkem Y, Wang B, Fish M, Haston S, Grabek A, Hallang S, Lodge EJ, Patist AL, Schedl A, Mollard P, Nusse R, Andoniadou CL. Pituitary stem cells produce paracrine WNT signals to control the expansion of their descendant progenitor cells. Elife. 2021 Jan 5;10:e59142. doi: 10.7554/eLife.59142. PMID: 33399538; PMCID: PMC7803373. 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 Jan 27;7(5):eabe4497. doi: 10.1126/sciadv.abe4497. PMID: 33571131; PMCID: PMC7840126. Zhang Z, Zamojski M, Smith GR, Willis TL, Yianni V, Mendelev N, Pincas H, Seenarine N, Amper MAS, Vasoya M, Cheng WS, Zaslavsky E, Nair VD, Turgeon JL, Bernard DJ, Troyanskaya OG, Andoniadou CL, Sealfon SC, Ruf-Zamojski F. Single nucleus transcriptome and chromatin accessibility of postmortem human pituitaries reveal diverse stem cell regulatory mechanisms. Cell Rep. 2022 Mar 8;38(10):110467. doi: 10.1016/j.celrep.2022.110467. PMID: 35263594; PMCID: PMC8957708.
White G, Velusamy A, Anandappa S, Masucci M, Breen LA, Joshi M, McGowan B, Hubbard JGH, Obholzer R, Christodoulou D, Jacques A, Touska P, Hassan FU, Izatt L, Carroll PV. Tumour detection and outcomes of surveillance screening in SDHB and SDHD pathogenic variant carriers. Endocr Connect. 2022 Feb 16;11(2):e210602. doi: 10.1530/EC-21-0602. PMID: 35060925; PMCID: PMC8859962. Williams ST, Chatzikyriakou P, Carroll PV, McGowan BM, Velusamy A, White G, Obholzer R, Akker S, Tufton N, Casey RT, Maher ER, Park SM, Porteous M, Dyer R, Tan T, Wernig F, Brady AF, Kosicka-Slawinska M, Whitelaw BC, Dorkins H, Lalloo F, Brennan P, Carlow J, Martin R, Mitchell AL, Harrison R, Hawkes L, Newell-Price J, Kelsall A, Igbokwe R, Adlard J, Schirwani S, Davidson R, Morrison PJ, Chung TT, Bowles C, Izatt L. SDHC phaeochromocytoma and paraganglioma: A UK-wide case series. Clin Endocrinol (Oxf). 2022 Apr;96(4):499-512. doi: 10.1111/cen.14594. Epub 2021 Sep 24. PMID: 34558728. Winzeler B, Tufton N, S Lim E, Challis BG, Park SM, Izatt L, Carroll PV, Velusamy A, Hulse T, Whitelaw BC, Martin E, Rodger F, Maranian M, Clark GR, A Akker S, Maher ER, Casey RT. Investigating the role of somatic sequencing platforms for phaeochromocytoma and paraganglioma in a large UK cohort. Clin Endocrinol (Oxf). 2022 Oct;97(4):448-459. doi: 10.1111/cen.14639. Epub 2021 Dec 6. PMID: 34870338; PMCID: PMC9543043.