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Professor Matt Smalley

Professor Matt Smalley

Professor, Director European Cancer Stem Cell Research Institute (ECSCRI)

School of Biosciences

Email:
smalleymj@cardiff.ac.uk
Telephone:
+44 (0)29 2087 5862
Location:
Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ
Media commentator

My group is trying to understand how the combination of different tumour-initiating genetic lesions occurring in different normal stem and progenitor cells drive cancer heterogeneity. Working both in breast and prostate cancer, we are interested both in inter-tumour heterogeneity – the clinical differences between tumours – as well as intra-tumour heterogeneity and the formation of cells with 'cancer stem cell' properties within a neoplasia. We are also trying to understand how the biological processes occurring in normal stem cells can be re-activated in tumours to drive de novo production of tumour cells with stem cell-like properties. We are using this information to identify novel therapeutic targets for blocking tumour growth, therapy resistance and metastasis.

Roles

  • Director, European Cancer Stem Cell Reseearch Institute
  • Co-Chair of the Wales Cancer Partnership Translational Research Committee
  • Deputy Head of Division of Biomedicine, School of Biosciences

Present and previous appointments

2018 – ongoing           Director, European Cancer Stem Cell Research Institute, Cardiff University.

2017 – ongoing           Professor, European Cancer Stem Cell Research Institute / School of Biosciences, Cardiff University.

2016 – 2017                Co-Director, Cancer Research UK Cardiff Research Centre.

2015 – ongoing           Deputy Head of Division of Biomedicine, School of Biosciences, Cardiff University.

2014 – 2017                Reader, European Cancer Stem Cell Research Institute / School of Biosciences, Cardiff University.

2013 – 2017                Deputy Director, European Cancer Stem Cell Research Institute.

2012 – 2014                Senior Lecturer, European Cancer Stem Cell Research Institute / School of Biosciences, Cardiff University.

2006 – 2011                Team Leader (Career Development Research Faculty), The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London.

2003 – 2005                Post-Doctoral Research Fellow, The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London.

2002 – 2003                EMBO Post-Doctoral Fellowship, Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

1997 – 2002                Post-Doctoral Research Fellow, Section of Cell and Molecular Biology, The Institute of Cancer Research, London.

1994 – 1997                Post-Doctoral Research Officer, Royal Postgraduate Medical School, Hammersmith Hospital, London.

 

Qualifications

1994                            PhD, Cell Biology, The Institute of Cancer Research, London.

1990                            BA (Hons, Upper Second Class), Zoology, Oxford University.

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Breast cancer is a highly heterogeneous disease. That heterogeneity is found both as inter- and intra-tumour heterogeneity. Inter-tumour heterogeneity can be classified on the basis of clinical parameters (e.g. grade, expression of hormone receptors), gene expression profiling and/or histological description (there are more than 20 different histological subtypes of breast cancer) and the biological basis for this heterogeneity is largely unknown. If we can understand this, we will not only have a better understanding of the basic biology of tumour development but it will also lead to better patient stratification and the development of targeted therapies for specific tumour subtypes.

Intra-tumour heterogeneity is shown by the multitude of different cell types found within a tumour. These can be described in terms of their appearance, e.g. epithelioid, spindle cells (EMT-like), squamoid, but also functionally. The most important of these functional classifications is into cells which possess stem cell-like features and cells which do not. Tumour cells which possess stem cell-like features ('cancer stem cells' or CSCs) may be responsible for maintaining the primary tumour as well as for seeding of metastases. Importantly, evidence is emerging that these functional populations may not have fixed identities but may be able to interconvert. Thus, if stem cell-like functions are to be targeted as a therapeutic strategy, it may be necessary to not only kill CSCs already present in the tumour but to block to conversion of non-CSCs to CSCs. One of the ways tumours may acquire stem cell-like functions is to re-activate and/or deregulate biological processes / signalling networks associated with normal stem/progenitor cells.

We are working with mouse models of breast cancer to address these issues. We are investigating how the same genetic lesions occurring in different stem/progenitor cells of origin can affect breast cancer heterogeneity. Conversely, we are studying how making different lesions in the same cell of origin activates different signalling networks to generate different tumour phenotypes. We have demonstrated that loss of the Brca1 tumour suppressor gene in luminal epithelial progenitors in the mammary gland, and not in basal stem cells, gives rise to tumours which phenocopy human BRCA1 breast cancers and the majority of non-familial basal-like breast cancers (Molyneux et al, Cell Stem Cell, 2010). We are now working with different combinations of Pten, Brca1, Brca2, p53 and Her2/Neu conditional alleles together with promoters that target basal stem cells, luminal estrogen receptor negative or luminal estrogen receptor positive cells.

We are also identifying key processes involved in regulation of normal mammary stem/progenitor cell behaviour. Following on from our detailed molecular analysis of mammary epithelial cell subpopulations (Kendrick et al, 2008), we identified the c-Kit signalling network as a regulator of mammary progenitor survival and proliferation (Regan et al, Oncogene, 2011). We also found that the Src family kinase Lyn, a downstream transducer of c-Kit signalling, is expressed in normal mammary progenitors and over-expressed in basal-like breast cancers (Molyneux et al, Cell Stem Cell, 2010; Regan et al, Oncogene, 2011). We are currently examining how Lyn deregulation may promote breast cancer formation and whether it is potential therapeutic target in this cell type.

Our expertise in isolation of mammary cell subpopulations (Sleeman et al, Breast Cancer Research, 2006; Sleeman et al, J Cell Biol, 2007; Britt et al, Breast Cancer Research, 2009; Regan et al, Oncogene, 2011) has enabled us to purify mammary stem cells away from other mammary cell populations, including other basal cell types, and carry out molecular profiling. We have identified a number of genes specifically expressed in the mammary stem cells and we are currently assaying them for their function in the biology of the normal mammary gland. If the genes are found to have important roles in the function of the normal stem cells, we will go on to determine whether their activity is deregulated in cancer stem cells and whether they have potential as therapeutic targets.

More recently, we have been working with mouse models of prostate cancer to both understand the molecular drivers of metastasis in this disease and also to use our models to test novel therapeutic approaches. In particular, we are working with collaborators on blocking the Wnt signalling pathway and the role of a cell surface molecule called PlexinB1 as a driver of metastasis.

Current grant support

  • Prostate Cancer Research Centre project grant
  • Breast Cancer Research Aid
  • Wales Cancer Research Centre
  • KESS studentship

Collaborators

  • Dr Mohamed Bentires-Alj (Friedrich Miescher Institute, Basel)
  • Dr Kate Hughes (Cambridge University)
  • Dr Niamh Buckley (Queen's University Belfast)
  • Dr Anita Grigoriadis (Kings College London)
  • Dr Maria dM Vivanco (University of Bilbao)
  • Dr Aamir Ahmed (Kings College London)
  • Dr Magali Williamson (Kings College London)
  • Dr Tim Robinson (Cardiff and Bristol Universities)

Affiliated staff

Postgraduate research students

  • Ms Manisha Dass (PhD student co-supervised with Dr Helen Pearson)