Endocrine Abstracts

Phaeochromocytomas are life-threatening catecholamine-producing tumours of the adrenal medulla. Our understanding of their pathogenesis is incomplete, with limited ability to predict malignant potential and disappointing treatment results in disseminated disease. Phaeochromocytomas occur in the inherited cancer syndrome von Hippel-Lindau (VHL). One function of VHL protein is in the formation and maintenance of primary cilia. These are microtubule-based organelles that protrude from cells, functioning in transduction of extracellular signals. This is dependent on localisation of signalling components to cilia, including pathways that are dysregulated in tumorigenesis. Moreover, cilia act as a checkpoint for cell division, because they assemble from the basal body, which is a modified centriole and thus required for spindle pole formation at the end of interphase. In this study we tested the hypothesis that primary cilia structure is disrupted in phaeochromocytomas and observed that primary cilia incidence and length is significantly reduced relative to normal adjacent tissue. This effect was greater in VHL patients compared to sporadic cases. Using the phaeochromocytoma-derived PC12 cell line we showed that abrogation of cilia, through knockdown of the ciliary protein IFT88, correlated with increased cell division, suggesting that cilia loss drives cellular proliferation. Next, we investigated whether hypoxia (a feature of the tumour microenvironment and specifically relevant to cluster 1 phaeochromocytomas) impacted on cilia function. Hypoxia resulted in the reduction of cilia incidence and length due to HIF-mediated increased activity of the HDAC6/AURKA cilia disassembly pathway. Pharmacological inhibition and siRNA-mediated knockdown of succinate dehydrogenase resulted in a ciliary phenotype that phenocopied the hypoxic response. Together, our data demonstrate that primary cilia dysfunction is a feature of phaeochromocytomas and identify a mechanism by which it occurs in cluster one tumours. This identification of primary cilia as a novel contributor to phaeochromocytoma pathogenesis represents a potential target for future therapeutic intervention.