The Role of Primary Cilia in the Molecular Pathogenesis of Phaeochromocytoma

Presentation Number: OR01-5
Date of Presentation: April 3rd, 2017

Samuel Matthew O'Toole*1, Umasuthan Srirangalingam1, William Drake1 and Paul Chapple2
1St Bartholomew's Hospital, London, United Kingdom, 2Queen Mary University London, London, United Kingdom


Understanding of phaeochromocytoma pathogenesis is incomplete with limited ability to predict malignant potential. Additionally, once metastatic, response to conventional therapies are disappointing.

Phaeochromocytomas are a common feature of the inherited cancer syndrome von Hippel-Lindau (VHL) disease, which is caused by loss of function of the VHL protein. As well as its canonical function in degradation of the transcription factor hypoxia-inducible factor, VHL is implicated in the formation and maintenance of primary cilia. These are microtubule-based organelles that protrude from nearly all cells and function in the transduction of extracellular signals. This is dependent on localisation of signalling components to cilia, including proteins linked to pathways that are dysregulated in tumorigenesis. Moreover, cilia are believed to 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, observing that incidence of primary cilia and ciliary length was reduced in sporadic and inherited phaeochromocytomas relative to normal adjacent tissue. This effect was most pronounced in cluster 1 phaeochromocytomas (e.g. VHL and SDHx) which display characteristic features of tissue 'pseudohypoxia'.

Using the phaeochromocytoma derived PC12 cell line we showed that abrogation of cilia, through knockdown of the ciliary protein IFT88 resulted in an increased rate of cell division. We then investigated if features of the tumour microenvironment impact on ciliary function. These studies revealed that hypoxic conditions and pseudohypoxia (stimulated by genetic and pharmacological loss of function of succinate dehydrogenase and protein VHL) result in disrupted cilia structure in the context of phaeochromocytoma. This effect is HIF-dependent and occurs via the HDAC6/AURKA ciliary disassembly pathway, inhibition of which prevents ciliary loss.

Together our data identify for the first time that primary cilia dysfunction is a feature of phaeochromocytomas, potentially contributing to pathogenesis and representing a target for therapeutic intervention.


Nothing to Disclose: SMO, US, WD, PC