Dr David Greenhalgh

Honorary Senior Research Fellow (School of Medicine, Dentistry & Nursing)

email: David.Greenhalgh@glasgow.ac.uk

Dermatology & Skin Cancer, School of Medicine, Dentistry & Nursing, R3.63, New Lister Building, Glasgow Royal Infirmary, G31 2ER

Import to contacts

https://orcid.org/0000-0002-6737-2744

Research interests

Analysis of the molecular mechanisms underlying cancer.

The development of cancer is a highly complex, multistage mechanism involving mutations in the genes that control cell growth and differentiation. My interests centre on exploiting the classic mouse model of multistage skin carcinogenesis to investigate mutations in oncogenes and tumour suppressor genes that initiate cancer; assess which gene combinations induced the promotion phase giving benign tumours and identify genes that achieve malignancy. In either tissue culture [i.e. living skin equivalents] or transgenic mouse skin, genetic engineering technologies coupled to topical steroid application enable us to induced mutations at specific times and mimic the acquisition of additional genetic insults that drives cancer development in humans. A recent highlight focused on investigation of ras and fos oncogene cooperation with PTEN tumour suppressor gene loss. The ras/PTEN cooperation model gave benign tumours but conversion to carcinoma involved consequences of PTEN loss not ras, an important result if ras was the therapeutic target. Further, fos/PTEN co-operation produced a “dead end” benign tumour [keratoacanthoma], due to re-expression of tumour suppressor genes p53 and p21, which prevented malignant conversion and thus identified compensatory anti-cancer surveillance mechanisms in benign tumours possibly amenable to therapeutic induction. Another arm studies melanoma, where we seek to understand the interactions between mutations in either melanocytes, keratinocytes or both that drive early disease. Ideally, once we identify the specific gene combinations implicated in this complex process, it may result in accurate models to aid in the design and testing of novel therapies.

Publications

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Number of items: 35.

2024

McMenemy, C. M. , Guo, D., Quinn, J. A. and Greenhalgh, D. A. (2024) 14-3-3σ/Stratifin and p21 limit AKT-related malignant progression in skin carcinogenesis following MDM2-associated p53 loss. Molecular Carcinogenesis, 63(9), pp. 1768-1782. (doi: 10.1002/mc.23771) (PMID:38869281)

2023

Gutierrez Crispini, A., Slosarska, A. and Greenhalgh, D. (2023) Inducible MDM2 Ablation Increases p53 Expression to Block Papillomatogenesis in HK1.ras Transgenic Mice. British Journal of Dermatology 189(1):e16. 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/ljad174.027)

Hardman-Carter, R., Lefkati, R., McMenemy, C. and Greenhalgh, D. (2023) Inducible 14-3-3 Sigma/Stratifin Ablation Cooperates with rasHa Activation to Accelerate Papillomatogenesis and Induce Malignant Conversion in Transgenic Mouse Skin Carcinogenesis. British Journal of Dermatology 189(1):e17–e18. 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/ljad174.032)

Moula, S., Greenhalgh, D. and Turnbull, G. (2023) Functional MDM2 Ablation in HK1.ras/fos-Δ5PTEN Transgenic Mice Results in an Elevated, p53-Mediated Block of Carcinogenesis that Depends upon p53 Expression. British Journal of Dermatology 189(1):e16. 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/ljad174.028)

Rawlinson, I., McMenemy, C. and Greenhalgh, D. (2023) Inducible 14-3-3 Sigma/Stratifin Ablation Accelerates Malignant Progression in HK1.ras/fos-Δ5PTENflx Transgenic Mouse Skin Carcinogenesis. British Journal of Dermatology 189(1):e21. 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/ljad174.040)

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)

2022

McMenemy, C. and Greenhalgh, D. A. (2022) Transgenic Epidermal 14-3-3σ/stratifin Overexpression Cooperates with Pten Ablation to Give a Limited Carcinoma In Situ Phenotype. British Journal of Dermatology 187(1):e21. Meeting Abstract: British Society for Investigative Dermatology Virtual Annual Meeting, 29–31 March 2021. (doi: 10.1111/bjd.20477)

Zaweia, R., McMenemy, C. , Quinn, J. and Greenhalgh, D. (2022) E-cadherin Loss Cooperates with RasHa Activation to Drive Malignant Progression in Transgenic Mouse Skin Carcinogenesis. British Journal of Dermatology 186(6):e232-e233. Meeting Abstract: British Society for Investigative Dermatology Annual Meeting, Frederick Douglass Centre, Newcastle University, Newcastle Upon Tyne, 4-6 April 2022. (doi: 10.1111/bjd.21248)

2020

Masre, S. F., Rath, N., Olson, M. F. and Greenhalgh, D. A. (2020) Epidermal ROCK2-induces AKT1/GSK3β/β-catenin, NFκB and dermal tenascin-C; but enhanced differentiation and p53/p21 inhibit papilloma. Carcinogenesis, 41(10), pp. 1409-1420. (doi: 10.1093/carcin/bgz205) (PMID:31907522) (PMCID:PMC7566339)

2019

Alyamani, A.M.A., Quinn, J.A. and Greenhalgh, D.A. (2019) Activated β-catenin Expression Inhibits Papillomas in HK1.ras Transgenic Mice Via Increased p53/p21-Associated Differentiation. British Journal of Dermatology 180(6): e186. Meeting Abstract: British Society for Investigative Dermatology Annual Meeting, Bradford, UK, 01-03 Apr 2019. (doi: 10.1111/bjd.17776)

McMenemy, C. , Quinn, J.A. and Greenhalgh, D.A. (2019) Epidermal-Specific 14-3-3σ/Stratifin Overexpressioninduces Malignant Conversion of Aggressive, Rapid-growth Papillomas, but not Slower, Regression-prone Papillomas. British Journal of Dermatology 180(6): e203. Meeting Abstract: British Society for Investigative Dermatology Annual Meeting, Bradford, UK, 01-03 Apr 2019. (doi: 10.1111/bjd.17776)

2018

Unbekandt, M. et al. (2018) Discovery of potent and selective MRCK inhibitors with therapeutic effect on skin cancer. Cancer Research, 78(8), pp. 2096-2114. (doi: 10.1158/0008-5472.CAN-17-2870) (PMID:29382705) (PMCID:PMC5901721)

Alyamani, A.M.A., Quinn, J.A. and Greenhalgh, D. A. (2018) Analysis of β-catenin expression in transgenic mouse skin carcinogenesis reveals inhibitory roles in papillomatogenesis and oncogenic roles in malignant conversion. BSID Annual Meeting 2018, London, UK, 26-28 Mar 2018.

Masre, S. F., Linkov, N., Olson, M. F. and Greenhalgh, D. A. (2018) Accelerated differentiation and p21/p53 responses to ROCK-mediated p-AKT/p-GSK3β/β-catenin overexpression prevent papillomas in transgenic mice. BSID Annual Meeting 2018, London, UK, 26-28 Mar 2018.

McMenemy, C. , Quinn, J.A. and Greenhalgh, D. A. (2018) Fos co-operation with 14-3-3σ [Stratifin] induces malignant conversion in transgenic mouse skin carcinogenesis: a paradigm for SCC of follicular origin. BSID Annual Meeting 2018, London, UK, 26-28 Mar 2018.

2017

Masre, S.F., Rath, N., Olson, M.F. and Greenhalgh, D.A. (2017) ROCK2/rasHa cooperation induce malignant conversion via p53 loss, elevated NF-κβ and tenascin C-associated rigidity but p21 inhibits ROCK2/NF-κβ-mediated progression. Oncogene, 36, pp. 2529-2542. (doi: 10.1038/onc.2016.402) (PMID:27991921)

McMenemy, C. , Guo, D., Cochrane, A., Crookston, K., Boyle, J., Quinn, J. and Greenhalgh, D. A. (2017) 14-3-3σ/Stratifin Expression in HK1.Ras/Fos-Δ5ptenflx Transgenic Mouse Skin Carcinogenesis Reveals an Early, Inhibitory Role; Lost During MDM2 Activated/P53 Inactivated Malignant Progression. British Society for Investigative Dermatology (BSID) Annual Meeting, Manchester, UK, 3-5 April 2017.

Tan, J., Mészáros, J., Young, L. and Greenhalgh, D. A. (2017) Inducible ß-Catenin Activation and PTEN Inactivation Elicit Follicular Tumours, Not Papillomas: A Potential Paradigm for Trichilemmomas in Cowden’s Disease. British Society for Investigative Dermatology (BSID) Annual Meeting, Manchester, UK, 3-5 April 2017.

2016

Samuel, M. S., Rath, N., Masre, S. F., Boyle, S. T., Greenhalgh, D. A. , Kochetkova, M., Bryson, S., Stevenson, D. and Olson, M. F. (2016) Tissue-selective expression of a conditionally-active ROCK2-estrogen receptor fusion protein. Genesis, 54(12), pp. 636-646. (doi: 10.1002/dvg.22988) (PMID:27775859)

Greenhalgh, D. A. (2016) Modelling Malignant Progression in Transgenic Mouse Skin Carcinogenesis. British Skin Foundation, Skin Deep - 20 Years of Research, 20th Anniversary Conference, London, UK, 13 Oct 2016. p. 44. (doi: 10.1111/bjd.14911)

Masre, S., Olson, M. and Greenhalgh, D. (2016) ROCK2 Activation Induces Malignant Conversion in rasHa-mediated Transgenic Mouse Skin Carcinogenesis Via p53 Loss, Elevated Nuclear Factor-κβ and Tenascin C-Associated Rigidity, but p21 Inhibits Early-Stage Progression. British Society for Investigative Dermatology Annual Meeting 2016, Dundee, 4 - 6 Apr 2016. (doi: 10.1111/bjd.14560)

2014

Macdonald, F., Yao, D., Quinn, J. and Greenhalgh, D. (2014) PTEN ablation in RasHa/Fos skin carcinogenesis invokes p53-dependent p21 to delay conversion while p53-independent p21 limits progression via cyclin D1/E2 inhibition. Oncogene, 33(32), pp. 4132-4143. (doi: 10.1038/onc.2013.372)

2013

Macdonald, F.H., Yao, D., Quinn, J.A. and Greenhalgh, D.A. (2013) Activated p-AKT, but not MDM2, drives malignant progression in Ras/Fos/PTEN^null skin carcinogenesis via p53/p21 loss and elevated cyclin D1/E2 expression. Journal of Investigative Dermatology, 133(S1), S57-S57. (doi: 10.1038/jid.2013.96)

Masre, S.F., Olson, M.F. and Greenhalgh, D.A. (2013) Inducible ROCK 2 activation increases primary keratinocyte differentiation but co-operates with ras^Ha activation in transgenic mouse skin carcinogenesis. Journal of Investigative Dermatology, 133(S1), S57-S57. (doi: 10.1038/jid.2013.96)

2011

MacDonald, F.H., Quinn, J.A. and Greenhalgh, D.A. (2011) Skin carcinogenesis in Ras/fos/PTEN^null transgenic mice associates reveals mTOR association with papillomatogenesis/conversion and AKT with malignant progression. British Journal of Dermatology, 164(4), p. 934. (doi: 10.1111/j.1365-2133.2011.10279.x)

2009

Greenhalgh, D. , Yao, D., Quinn, J. and Macdonald, F. (2009) RasHa activation interdicts compensatory p53/p21WAF expression in Fos/PTENnull skin carcinogenesis via initial p53 loss but retention of p21WAF limits malignant progression. In: American Association for Cancer Research (AACR) 100th Annual Meeting, Denver, USA, 18-22 April 2009,

Macdonald, F., Yao, D., Quinn, J. and Greenhalgh, D. (2009) Compensatory p53/p21WAF-induced differentiation in Fos/PTENnull skin carcinogenesis is interdicted by RasHa activation but retention of p21WAF inhibits malignant progression. In: British Society for Investigative Dermatology (BSID) Annual Meeting, Royal Agricultural College, Cirencester, UK, 30 March - 1 April 2009,

2008

Yao, D., Alexander, C.L., Quinn, J., Chan, W.-C., Wu, H. and Greenhalgh, D.A. (2008) Fos co-operation with PTEN loss elicits keratoacanthoma not carcinoma due to p53/p21^WAF-induced differentiation triggered by GSK3b inactivation and reduced AKT activity. Journal of Cell Science, 121(10), pp. 1758-1769. (doi: 10.1242/jcs.021147)

Yao, D., Alexander, C., Quinn, J. , Chan, W., Wu, H. and Greenhalgh, D. (2008) Fos cooperation with PTEN loss elicits keratoacanthoma not carcinoma, owing to p53/p21(WAF)-induced differentiation triggered by GSK3 beta inactivation and reduced AKT activity. Journal of Cell Science, 121(10), pp. 1758-1769.

2006

Yao, D., Alexander, C.L., Quinn, J.A., Porter, M.J., Wu, H. and Greenhalgh, D.A. (2006) PTEN loss promotes ras^Ha-mediated papillomatogenesis via dual up-regulation of AKT activity and cell cycle deregulation but malignant conversion proceeds via rasHa-independent pathways. Cancer Research, 66(3), pp. 1302-1312.

Shaw, M., Yao, D., Quinn, J.A. and Greenhalgh, D.A. (2006) Paradoxical maintenance of E-cadherin following inducible PTEN ablation in Ras or Fos-mediated skin carcinogenesis identifies sentinel mechanisms geared to combat PTEN dysfunction. In: British Society for Investigative Dermatology Annual Meeting, Manchester, 10-12 April 2006, p. 247. (doi: 10.1111/j.1365-2133.2006.07327.x)

Yao, D., Alexander, C., Quinn, J., Porter, N., Wu, H. and Greenhalgh, D. (2006) PTEN loss promotes ras(Ha)-mediated papillomatogenesis via dual up-regulation of AKT activity and cell cycle deregulation but malignant conversion proceeds via PTEN-associated pathways. Cancer Research, 66, pp. 1302-1312. (doi: 10.1158/0008-5472.CAN-05-2341)

2005

Yao, D., Quinn, J.A. and Greenhalgh, D.A. (2005) Inducible cre-mediated N-ras activation and PTEN inactivation in transgenic mouse melanocytes requires keratinocyte hyperplasia to elicit a melanocyte pathology. In: Montagne Symposia, 2004 and 6th International Skin Cancer Conference, 2004, Salishan Resort, Newport, Oregon, USA, Oct 2004, p. 171.

2003

Bakirtzis, G. et al. (2003) Targeted epidermal expression of mutant Connexin 26(D66H) mimics true Vohwinkel syndrome and provides a model for the pathogenesis of dominant connexin disorders. Human Molecular Genetics, 12, pp. 1737-1744. (doi: 10.1093/hmg/ddg183)

Bakirtzis, G., Jamieson, S. , Aasen, T., Bryson, S., Forrow, S., Tetley, L., Finbow, M., Greenhalgh, D. and Hodgins, M. (2003) The effects of a mutant connexin 26 on epidermal differentiation. Cell Communication and Adhesion, 10(4-6), pp. 359-364. (doi: 10.1080/cac.10.4-6.359.364)

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