Understanding how EDAR signalling modulates susceptibility to skin and colorectal cancer

Abstract

The Ectodysplasin A Receptor (EDAR) signalling pathway is essential during skin development. EDAR signalling deficiencies result in diseases such as Hypohidrotic Ectodermal Dysplasia (HED) - characterised by lack of skin-derived structures such as hair, teeth and glands, which results in inability to thermoregulate. As a result, much of EDAR-related research has focused on pathway activation in the context of skin, with drugs in development and patents approved for EDAR pathway stimulation. Given that EDAR signalling cross-talks with cancer-associated pathways such as Wnt, we aimed to understand the role EDAR signalling plays in cancer. This was an important novel investigation, given that East Asian and Native American populations express hyperactive EDAR variant forms and thus may display altered cancer susceptibilities. Furthermore, clinical trials and cancer research tools are predominated by ethnically European patients and associated samples. This thesis therefore provides a rare exploration into population differences in cancer. Using publicly-available human patient data - across various ethnic populations - as well as EDAR-overexpressing in vivo and in vitro methods, we modelled cutaneous Squamous Cell Carcinoma (cSCC) and colorectal cancers expressing the hyperactive EDAR variant (as in East Asian and Native American populations) or the ancestral EDAR form (as in European ethnic populations). This is the first time EDAR has been studied in the context of skin SCC, and only the second time in colorectal cancer. We discovered that whilst EDAR signalling delays and reduces tumour incidence, high EDAR activity or expression encourages more squamous, invasive, and metastatic tumours to develop. Moreover, high EDAR expression induces immune suppressive environments in cSCC - indicating a potentially reduced response to immunotherapies with high EDAR. Importantly, survival from cancer is reduced with high EDAR expression. This presents EDAR as a novel oncogene and renders patients with high expression or activity of EDAR at greater risk of aggressive cancers and early death. Together, this emphasises the need to move towards genotype-based treatment approaches and to develop EDAR-inhibitory drugs to promote patient survival - particularly in individuals with high EDAR activity and/or expression. Finally, this warns against chronic use of EDAR-activating agents that exist for treatment of disorders such as hair loss, given our identification of EDAR as a novel oncogene.

Date of Award	6 Jan 2025
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Keith Brennan (Supervisor) & Katie Finegan (Supervisor)