ECE2023 Oral Communications Oral Communications 9: Adrenal and Cardiovascular Endocrinology 2 (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 1 , Thea Willis 1 , James Kaufman-Cook 1 , Emily Lodge 1 , Val Yianni 1 , Rebecca J. Oakey 1 & Cynthia L. Andoniadou 1,2
1King’s College London, London, United Kingdom; 2Dresden University of Technology, 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 and in adulthood in adrenomedullary sustentacular cells. Using the inducible Sox2-CreERT2 driver, in vivo lineage tracing in neonates and adults demonstrates that murine neural crest-derived SOX2+ cells expand to self-renew and give rise to new chromaffin, 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.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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