Inducible E-cadherin Ablation Drives Malignant Progression in HK1.ras.fos.PTENflx/flx Carcinogenesis and Induces Conversion of HK1.fos.PTENflx/flx Keratoacanthoma

Zaweia, R., Alyamani, A., McMenemy, C. , Quinn, J. and Greenhalgh, D. (2023) Inducible E-cadherin Ablation Drives Malignant Progression in HK1.ras.fos.PTENflx/flx Carcinogenesis and Induces Conversion of HK1.fos.PTENflx/flx Keratoacanthoma. British Journal of Dermatology 189(1):e23. Meeting Abstract: British Society for Investigative Dermatology (BSID) Annual Meeting, Technology & Innovation Centre, University of Strathclyde, Glasgow, Scotland, 20–21 March 2023. (doi: 10.1093/bjd/ljad174.044)

Abstract

Inducible ablation of E-cadherin expression has been investigated in mouse skin carcinogenesis driven by Ras and Fos activation (HK1.ras; HK1.fos), and conditional (cre/lox) PTEN knockout exclusively in the epidermis. Previously, analysis of endogenous E-cadherin expression in stage-specific HK1.ras/fos/Δ5PTEN tumours showed E-cadherin expression became reduced at the invasive front of well-differentiated squamous cell carcinomas (wdSCCs) following p53 loss, and where retention of p21 minimized Akt activation and further progression. To validate stage-specific causality of E-cadherin loss, RU486-inducible conditional E-cadherin knockout was introduced into HK1.ras/fos/Δ5PTENflx/flx genotypes employing the cre/LoxP system (K14cre-ΔE-cadflx/flx). Initial observations in RU486-treated compound HK1.ras/fos/ΔPTENflx/flx-ΔE-cadflx/flx mice found that E-cadherin ablation appeared to accelerate malignant conversion, again associated with p53 loss; however, the main effect was on malignant progression and invasion, as wdSCCs displayed rapid progression to aggressive SCCs. Malignant progression also implicated β-catenin activation, finding increased nuclear expression, alongside loss of membranous expression, in the invasive basal layer keratinocytes, together with loss of p21 and increased p-Akt1 activity. In addition, preliminary data for E-cadherin loss in HK1.fos/Δ5PTEN keratoacanthoma aetiology now showed malignant conversion to invasive wdSCC, again associated with increased β-catenin activation. These wdSCCs may have retained a degree of correct adhesion signalling, as basal layer HK1.fos/Δ5PTEN-ΔE-cadflx/flx keratinocytes exhibited both membranous and nuclear p-β-catenin expression; hence, in the absence of Ras, progression stalled at wdSCC. Collectively, these data show that, in some contexts (hyperplasia/papillomas), E-cadherin loss can be tolerated via increased differentiation, while in carcinogenesis, following overt tumour appearance, conditional ablation of E-cadherin drives invasion and malignant progression, consistent with roles in cell–cell adhesion and deregulated signalling to β-catenin.

• Item Type: Conference or Workshop Item
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Greenhalgh, Dr David and Alyamani, Abdullah Mohammad A and Quinn, Dr Jean and ZAweia, Rema Mahmud M and MCMENEMY, Carol
• Authors: Zaweia, R., Alyamani, A., McMenemy, C., Quinn, J., and Greenhalgh, D.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
• ISSN: 0007-0963