Dr Matthew Caley, PhD, MRes, BSc (Hons)

Profile

Matthew received his PhD in Biological Sciences from Cardiff University in 2008 studying Chronic Wounds under the supervision of Prof. Phil Stephens. He then moved to Imperial College London joining the laboratory of Dr Justin Sturge and Prof. Jonathan Waxman to study prostate cancer metastasis and the role the extracellular matrix plays in controlling cell behaviour.

In 2011, he moved to the Blizard Institute returning to skin research in the laboratory of Prof. Edel O’Toole. His research has focussed on the skin basement membrane and investigating its role in healthy and damaged skin as well as in skin cancer.

In 2019 Matthew was appointed as a Lecture in Cell Biology.

Group Members

• Dr Eleri Jones  

Centre: Cell Biology and Cutaneous Research

Websites:

• LinkedIn - Matthew Caley
• Twitter - @matcaley

Teaching

Undergraduate

Course Lecturer: BIO111 Cell Biology

Course Lecturer: BIO115 The Human Cell

MBBS – Problem Based Learning

Supervisor MedPro

Postgraduate

MSc Regenerative Medicine

Module Lead: ICM714 Tissue Specific Stem Cells, MSc Regenerative Medicine

Course Lecturer: ICM7141 Cell and Molecular Basis of Regeneration, MSc Regenerative Medicine

Project Supervisor: MSc Regenerative Medicine

Research

Research Interests:

The basement membrane zone (BMZ), present in all epithelia, plays an important role in maintaining normal tissue homeostasis. It does this not only through offering structural support for cells but also by signalling through cell surface receptors. Components of the BMZ include collagens IV, VII and XVII as well as laminin 332.

Laminin 332

Laminin is a three-chained glycoprotein which is copiously secreted by epithelial and endothelial cells. Within the basement membrane the primary laminin is laminin 332. Mature laminin 332 is made up of three separate proteins an alpha (Lamɑ2), beta (Lamβ2) and gamma chain (Lamγ2). Loss of any chain disrupts the mature protein. Recent work in this laboratory has demonstrated an important role for laminin 332 in squamous cell carcinoma, cholesterol transport and in immune regulation. Laminin 332 is specifically degraded by proteases during normal tissue remodelling or tumour invasion. MT1-MMP, MMP2 and BMP-1 have all been shown to degrade laminin 332^1,2. Intact and cleaved laminin 332 are recognised by cell surface integrin receptors ɑ3β1 and ɑ6β4 which are expressed on a range of cells including macrophages³.

Projects

Repairing the skin barrier in Junctional Epidermolysis Bullosa

Junctional epidermolysis bullosa (JEB) is a rare genetic skin disorder leading to severe skin fragility from birth. It is caused by mutations in genes encoding the skin basement membrane proteins. The most severe form, JEB generalised severe, is caused by a complete loss of one of the parts of laminin 332. Babies diagnosed with this form of JEB do not survive beyond their first birthday⁴.

We have discovered a previously unreported characteristic of JEB skin, a loss of skin lipids especially cholesterol within the skin of JEB patients. Within the skin cholesterol plays an important role in maintaining the skin barrier preventing water loss, skin infection and dry skin related itch. Using models of JEB skin as well as patient samples we have identified a defect in cholesterol transport. JEB cells can make cholesterol but are unable to transport it out of the cell which leads to the loss of lipids within JEB skin. Cholesterol transport has been extensively studied within the liver and drugs developed to decrease blood cholesterol by increasing cholesterol transport.

The role of the Laminin 332-Actin-Cholesterol axis in skin conditions with altered lipid profiles

The skin’s epidermal barrier plays a vital role in protecting the body from excessive water loss, environmental chemicals and microbial infection. The stratum corneum (SC) barrier is formed of flattened keratin rich corneocytes surrounded by intercellular lipid bilayers.

The skin barrier can be disrupted by injury, underlying genetic conditions, inflammation, environmental changes and by age leading to dry, easily damaged skin. Investigations of dry skin have identified increased corneocytes accumulation as well as alterations in both the composition of SC lipids and their total abundance.

How does the loss of Laminin 332 affect the tumour microenvironment?

Squamous cell carcinoma is the second most common cancer of the skin (after basal cell carcinoma) and despite acknowledged under-reporting there are almost 100,000 new cases of non-melanoma skin cancers (NMSC) recorded in the UK each year of which 20% are SCC (www.cruk.org). SCC has a number of associated risk factors linked with tumour initiation including UV exposure, HPV infection and the immunocompromised state eg in transplant patients⁵. The primary treatment for SCC is surgical excision. There is a 4% risk of metastasis, but this risk increases to 16% if the initial tumour is thicker than 6mm⁶. The tumour microenvironment is a complex assembly of multiple different cell types, extracellular matrix (ECM) components and growth factors. The interplay between these different components influences tumour growth, aggression and resistance to treatment^7,8. To model this complex microenvironment, tumours are increasingly studied using animal spontaneous cancer models or xenografts. The (ECM), and in particular the basement membrane, acts as a barrier to tumour invasion as well as a source of growth factors and signals when broken down by invading tumour cells. In the tumour microenvironment, ECM and basement membrane components are secreted by both non-malignant and cancer cells, creating a unique tumour ECM⁹. Both healthy and tumour ECM are made up of a mixture of secreted molecules including collagens, elastin, fibronectin and laminin¹⁰. Changes in laminin 332 protein expression have been observed in a wide range of tumours with both an increase and decrease associated with poor prognosis^11-17. Mutations in laminin 332 cause the severe blistering disease junctional epidermolysis bullosa (JEB). This project will investigate the role of the basement membrane protein Laminin 332 in controlling tumour progression, invasion and the recruitment of macrophages in SCC. The main hypothesis is that laminin 332 acts as a regulator of tumour invasion and macrophage recruitment.

1. Amano S, Scott IC, Takahara K et al. Bone morphogenetic protein 1 is an extracellular processing enzyme of the laminin 5 gamma 2 chain. The Journal of biological chemistry 2000; 275: 22728-35.
2. Koshikawa N, Minegishi T, Sharabi A et al. Membrane-type matrix metalloproteinase-1 (MT1-MMP) is a processing enzyme for human laminin gamma 2 chain. The Journal of biological chemistry 2005; 280: 88-93.
3. Ammon C, Meyer SP, Schwarzfischer L et al. Comparative analysis of integrin expression on monocyte-derived macrophages and monocyte-derived dendritic cells. Immunology 2000; 100: 364-9.
4. Hammersen J, Has C, Naumann-Bartsch N et al. Genotype, Clinical Course, and Therapeutic Decision Making in 76 Infants with Severe Generalized Junctional Epidermolysis Bullosa. The Journal of investigative dermatology 2016; 136: 2150-7.
5. Arlette JP, Trotter MJ. Squamous cell carcinoma in situ of the skin: history, presentation, biology and treatment. The Australasian journal of dermatology 2004; 45: 1-9; quiz 10.
6. Brantsch KD, Meisner C, Schonfisch B et al. Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study. The lancet oncology 2008; 9: 713-20.
7. Marinkovich MP. Tumour microenvironment: laminin 332 in squamous-cell carcinoma. Nature reviews. Cancer 2007; 7: 370-80.
8. Lu P, Weaver VM, Werb Z. The extracellular matrix: a dynamic niche in cancer progression. The Journal of cell biology 2012; 196: 395-406.
9. Engbring JA, Kleinman HK. The basement membrane matrix in malignancy. The Journal of pathology 2003; 200: 465-70.
10. Charonis A, Sideraki V, Kaltezioti V et al. Basement membrane peptides: functional considerations and biomedical applications in autoimmunity. Current medicinal chemistry 2005; 12: 1495-502.
11. Miyazaki K. Laminin-5 (laminin-332): Unique biological activity and role in tumor growth and invasion. Cancer science 2006; 97: 91-8.
12. Lyons AJ, Jones J. Cell adhesion molecules, the extracellular matrix and oral squamous carcinoma. International journal of oral and maxillofacial surgery 2007; 36: 671-9.
13. Nakayama M, Sato Y, Okamoto M et al. Increased expression of laminin-5 and its prognostic significance in hypopharyngeal cancer. The Laryngoscope 2004; 114: 1259-63.
14. Moriya Y, Niki T, Yamada T et al. Increased expression of laminin-5 and its prognostic significance in lung adenocarcinomas of small size. An immunohistochemical analysis of 102 cases. Cancer 2001; 91: 1129-41.
15. Lohi J, Oivula J, Kivilaakso E et al. Basement membrane laminin-5 is deposited in colorectal adenomas and carcinomas and serves as a ligand for alpha3beta1 integrin. APMIS : acta pathologica, microbiologica, et immunologica Scandinavica 2000; 108: 161-72.
16. Aoki S, Nakanishi Y, Akimoto S et al. Prognostic significance of laminin-5 gamma2 chain expression in colorectal carcinoma: immunohistochemical analysis of 103 cases. Diseases of the colon and rectum 2002; 45: 1520-7.
17. Shinto E, Tsuda H, Ueno H et al. Prognostic implication of laminin-5 gamma 2 chain expression in the invasive front of colorectal cancers, disclosed by area-specific four-point tissue microarrays. Laboratory investigation; a journal of technical methods and pathology 2005; 85: 257-66.

Publications

Key Publications

Enjalbert, F., Dewan, P., Caley, M. P., Jones, E. M., Morse, M. A., Kelsell, D. P., . . . O'Toole, E. A. (2020). 3D model of harlequin ichthyosis reveals inflammatory therapeutic targets.. J Clin In-vest. doi:10.1172/JCI132987

Caley, M. P., King, H., Shah, N., Wang, K., Rodriguez-Teja, M., Gronau, J. H., . . . Sturge, J. (2016). Tumor-associated Endo180 requires stromal-derived LOX to promote metastatic prostate cancer cell migration on human ECM surfaces. Clinical and Experimental Metastasis, 33(2), 151-165. doi:10.1007/s10585-015-9765-7

Martins, V. L., Caley, M. P., Moore, K., Szentpetery, Z., Marsh, S. T., Murrell, D. F., . . . O'Toole, E. A. (2015). Suppression of TGFβ and Angiogenesis by Type VII Collagen in Cutaneous SCC.. J Natl Cancer Inst, 108(1). doi:10.1093/jnci/djv293

Palmieri, C., Caley, M. P., Purshouse, K., Fonseca, A. -V., Rodriguez-Teja, M., Kogianni, G., . . . Sturge, J. (2013). Endo180 modulation by bisphosphonates and diagnostic accuracy in met-astatic breast cancer.. Br J Cancer, 108(1), 163-169. doi:10.1038/bjc.2012.540

Caley, M. P., Kogianni, G., Adamarek, A., Gronau, J. H., Rodriguez-Teja, M., Fonseca, A. -V., . . . Sturge, J. (2012). TGFβ1-Endo180-dependent collagen deposition is dysregulated at the tumourstromal interface in bone metastasis.. J Pathol, 226(5), 775-783. doi:10.1002/path.3958

All Publications

Supervision

• Sarah Hindle (Second/Additional Supervisor)
• Rotimi Dina (Second/Additional Supervisor)