E-cadherin loss cooperates with ras(Ha) activation to drive malignant progression in transgenic mouse skin carcinogenesis
Zaweia, R. McMenemy, Carol Quinn, J. Greenhalgh, D.
Zaweia, R.
McMenemy, Carol
Quinn, J.
Greenhalgh, D.
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Abstract
To investigate the stage at which E-cadherin loss may drive carcinogenesis, 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. Analysis of endogenous E-cadherin expression in stage-specific HK1.ras/fos/Δ5PTEN tumours found increased levels in papilloma basal layer keratinocytes, but following p53 loss and subsequent malignant conversion, E-cadherin expression became reduced at the invasive front of resultant, well-differentiated, squamous cell carcinomas (wdSCCs). To validate the causality of this E-cadherin loss observed in malignant progression, RU486-inducible, conditional E-cadherin knockout was introduced into regression-prone papillomas exhibited by HK1.ras mice, employing the cre/LoxP system (K14cre.ΔE-cadflx/flx). Initial observations in RU486-treated K14cre.ΔE-cadflx/flx mice found that E-cadherin ablation induced a mild hyperplasia, with some altered differentiation in basal layer and follicular keratinocytes but no tumours. In contrast, while E-cadherin loss in HK1.ras.K14cre.ΔE-cadflx/flx mice did not appear to alter HK1.ras-mediated papillomatogenesis, malignant conversion was now observed and, moreover, subsequent wdSCCs showed a rapid progression to aggressive SCC. Further analysis found that malignant conversion was associated with p53 loss, while malignant progression also implicated β-catenin activation; increased nuclear expression appeared in the invasive basal layer keratinocytes. The SCC aetiology also suggested the mechanism of tumour invasion may involve an early collective mode and later, in cooperation with β-catenin activation, this progressed to a more aggressive mode of individual cell invasion. Collectively, these data show that conditional ablation of E-cadherin cooperates with rasHa activation and p53 loss at later stages following malignant conversion of papillomas, to induce a rapid tumour progression due to cell–cell adhesion failures and β-catenin signalling.
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Date
2022
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Collections
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Meetings and Proceedings