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Endocrine Abstracts (2022) 86 OC4.2 | DOI: 10.1530/endoabs.86.OC4.2

SFEBES2022 Oral Communications Adrenal and Cardiovascular (6 abstracts)

Generation of novel tools for the study and development of targeted therapeutic approaches for pheochromocytoma and paraganglioma

Yasmine Kemkem 1 , Alice Santambrogio 1 , Bertille Montibus 2 , Carlos Abascal Sherwell Sanchez 1 , Thea L. Willis 1 , Emily J. Lodge 1 , Val Yianni 1 , Rebecca J. Oakey 2 & Cynthia L. Andoniadou 1,3


1Centre for Craniofacial and Regenerative Biology, King’s College London, London, United Kingdom; 2Department of Medical and Molecular Genetics, King’s College London, London, United Kingdom; 3Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany


Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours, which arise from neural crest (NC)-derived structures: the adrenal medulla and the paraganglia. Around one third of PPGLs are associated with inherited cancer susceptibility genes, the highest rate among all tumour types. Currently, the only diagnostic criterion for malignant disease is the presence of metastasis and no molecular or histological features have been identified that help predict risk. Additionally, understanding the pathogenesis of PPGLs and development of new therapies is hindered by the lack of validated disease models. In many tumours, cancer cells with stem-like properties are at the root of tumour initiation/maintenance due to their ability to self-renew and proliferate, but a stem cell population of the adrenal medulla has not been identified. We show that SOX2, a well-characterised marker of multiple stem cell populations, is expressed in a subset of uncommitted Schwann-cell precursors, which generate chromaffin cells and sympathetic neurons and that SOX2 expression persists postnatally in adrenomedullary sustentacular cells. Using the inducible Sox2-CreERT2 driver, in vivo lineage tracing demonstrates that murine neural crest-derived SOX2+ cells expand to self-renew and give rise to new chromaffin cells throughout life, supporting their function as a novel progenitor/stem cell population. This population is therefore ideal to target for expression of tumour-inducing mutations, to generate transgenic models of PPGLs. We establish a system to isolate and culture pure murine and human populations of adrenomedullary SOX2+ stem cells in vitro and demonstrate that these cells can be expanded and gene-edited, to express mutant forms of Succinate Dehydrogenase subunits (SDHx), responsible for most hereditary PPGL cases. Finally, normal and mutated SOX2+ adrenomedullary stem cells can be implanted in vivo onto the chick chorioallantoic membrane (CAM), where they can be assayed for expansion, contribution of chromaffin cells and tumourigenic properties including invasion and metastasis.

Volume 86

Society for Endocrinology BES 2022

Harrogate, United Kingdom
14 Nov 2022 - 16 Nov 2022

Society for Endocrinology 

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