OC7.6 - ECE_2870 - SOX2-positive cells in pheochromocytoma and paraganglioma: implications for tumour initiation and maintenance

Le résumé fourni par la source

Abstract Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare neuroendocrine tumours which arise from neural crest–derived chromaffin cells of the adrenal medulla and extra-adrenal paraganglia, respectively. Metastatic disease occurs in up to 40% of PPGLs and is associated with a median overall survival of seven years. Despite advances in the molecular characterisation of PPGLs, progress in prognostic stratification and the development of targeted therapies remains limited, reflecting an incomplete understanding of the cellular mechanisms underlying tumour initiation and progression. In several malignancies, tumour growth and dissemination are sustained by cells with stem-like properties, due to their ability to self-renew and give rise to differentiated cells. We have recently shown that, in the human adrenal, a subset of sustentacular cells are postnatal adrenomedullary stem cells expressing the stem cell transcription factor SOX2, specified along the neural crest migratory trajectory. In this study, we investigated whether SOX2-positive cells in PCCs and PGLs display features consistent with a tumour-initiating cell population. Using transcriptomic profiling of 10 published and 3 new tumour datasets and expression analyses of an additional cohort of 19 tumours, we demonstrate the presence of SOX2-expressing cells across a broad range of PPGLs independent of tumour location, aggressiveness, or underlying genetic mutation. Transcriptomic analyses reveal a highly proliferative cell population co-expressing SOX2 and chromaffin cell markers. To determine whether expression of SOX2 is sufficient to promote proliferation, we overexpressed Sox2 in PC12 cells, a well-characterised rat pheochromocytoma cell line. Cell cycle analysis showed that Sox2 expression does not confer a proliferative advantage, supporting its role in PPGL as a stem cell hallmark. However, PPGLs enriched in SOX2+ cells showed differential expression of several genes encoding pro-tumourigenic paracrine factors. Ligand-receptor analysis further confirmed signalling from tumour chromaffin cells to other cell populations. In summary, in silico analyses support that tumours enriched in proliferative SOX2+ chromaffin tumour cells have distinct oncogenic gene expression and a secretory signature consistent with cancer promotion. This suggests both a direct contribution and an indirect paracrine role of SOX2+ tumour chromaffin cells in PPGL tumour maintenance. Isolation of SOX2-positive PPGL cells under stem cell–promoting conditions, followed by xenotransplantation onto the chicken chorioallantoic membrane, demonstrated their capacity for expansion and metastatic behaviour in ovo, confirming their tumour-initiating potential. This study redefines the cellular origins of PPGLs by identifying SOX2-positive tumour cells with tumour-initiating potential. These findings may inform improved PPGL tumour stratification and offer new avenues for therapy.

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