Dr Nicole Bechmann, Prof. Ben Wielockx, TUD, Dresden International Graduate School for Biomedicine and Bioengineering, Cynthia Andoniadou PhD, King’s, Centre for Craniofacial and Regenerative Biology and Andoniadou Lab
Phaeochromocytomas and paragangliomas (PPGLs) are catecholamine-producing tumours growing in with distinguished phenotypic features. Pseudohypoxic cluster 1 PPGLs are characterised by an activation of hypoxia-pathways mainly due to an increased expression and stabilisation of hypoxia inducible factor (HIF) 2α and show an undifferentiated phenotype (immature catecholamines), while cluster 2 PPGLs exhibit a differentiated phenotype.
Our previous work suggests that the interaction of HIFs with the MYC/MAX complex play a significant role in this regard. Furthermore, the work of Das et al. (2019) indicates that the transcription factor SOX2 may also influence the interaction between HIF2α and MYC, thereby regulating cell differentiation and self-renewal. Therefore, we hypothesised that SOX2 interacts with the HIF-MYC/MAX complex and thereby substantially contributes to the regulation of phenotypic features in PPGLs.
Initially, tumour and normal adrenal tissue of PPGL patients will be examined with regard to the co-expression of SOX2, HIF2, MYC and MAX (immunohistochemistry) and subsequently the expression will be correlated with differentiation markers such as PNMT. Available mouse strains allow manipulation of Hif2α (Prof. Wielockx, TUD/MF) in Sox2 cells (Dr. Andoniadou, King’s) and help elucidate our understanding of underlying mechanisms. State-of-the-art technology for genetic manipulation will be applied to regulate the expression of Myc and Sox2 in mouse phaeochromocytoma cells in the presence or absence of Hif2α expression.
This project will contribute significantly to our understanding of the molecular mechanisms involved in the regulation of phenotypic characteristics in PPGLs. This may lead to the identification of novel therapeutic strategies to improve the outcome of these patients.