Professor Matthew Smalley

BA (Hons) (Oxon) PhD

Publication

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Research

Cancer is a highly heterogeneous disease and breast cancer is a classic example of this. That heterogeneity is found both as inter- and intra-tumour heterogeneity. Inter-tumour heterogeneity in breast cancer 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 in humans). Intra-tumour heterogeneity, in contrast, 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. Functionally heterogeneous cells may be responsible for maintaining the primary tumour as well as for seeding of metastases and conferring on the tumour resistance to therapeutic interventions (although not all cells may show all these properties). Importantly, these functional populations do not have fixed identities, but may arise de novo in the tumour and also evolve in response to selective pressures, representing a moving target for therapy.

In previous work, we used mouse models of breast cancer to investigate how the same genetic lesions occurring in different stem/progenitor cells of origin can affect breast cancer heterogeneity. We have also studied 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 estrogen receptor negative epithelial stem/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). Indeed, we have also demonstrated that this same population is likely the cell of origin for the majority of estrogen-receptor low/negative breast cancers (Melchor et al, J Pathology, 2014).

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, 2012) enabled us to purify mammary stem cells away from other mammary cell populations, including other basal cell types, and carry out molecular profiling. We identified a number of genes specifically expressed in the mammary stem cells and demonstrated that the mammary stem cell gene expression profile is highly prognostic for metastasis-free survival in triple-negative breast cancer patients (Sleeman et al, Breast Cancer Research, 2015).

Working more mechanistically, we identified 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, 2012). 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, 2012). We have shown that in BRCA1-loss-of-function-associated breast cancer, LYN activity is uncoupled from activation by c-KIT. Rather, BRCA1 loss results in upregulation of a prolyl isomerase, PIN1, which interacts with and activates LYN, most likely by changing its conformation into an active state (Tornillo et al, Cell Reports, 2018). We have also shown that the balance of splice isoforms of LYN is altered in aggressive breast cancers, and that the longer isoform, LYN-A, promotes breast cancer cell migration and invasion (Tornillo et al, Cell Reports, 2018). However, genetic deletion of LYN in tumour cells from BRCA1-loss-of-function-associated breast cancer had little difference on tumour behaviour. Rather, the extent of immune cell infiltration into the tumour was a better predictor of tumour behaviour (Tornillo et al, Disease Models Mechanisms 2024).

We have now expanded our interests to try and understand what are the genetic factors which predispose individuals to getting one sort of cancer and not another, using the genetics of domestic dog breeds as a model system. As a first step, we have worked with veterinary oncologists, pathologists and epidemiologists to understand the breed phenotypes linked to different sorts of cancer, particularly canine mammary cancer (which is an excellent model for human breast cancer, although with some caveats) and osteosarcoma.

We have shown that osteosarcoma risk increases with increasing body mass, but also that long-skulled (dolichocephalic) dogs are at higher risk than flat-faced (brachycephalic) dogs (Edmunds et al, Canine Medicine and Genetics, 2021) (see figure below).

Figure Legend: Breed skull shape and OR for osteosarcoma risk plotted against mean body mass. Body mass was calculated as the mean of the VetCompass estimates of average mass for males and females of each breed. Ak(u), Akita (Unspecified); AM, Alaskan Malamute; AB, American Bulldog; Be, Beagle; BF, Bichon Frise; BC, Border Collie; BT, Border Terrier; Bo, Boxer; Bu(u), Bulldog (Unspecified); CT, Cairn Terrier; CKCS, Cavalier King Charles Spaniel; CS, Cocker Spaniel; Co(u), Collie (Unspecified); Da, Dalmatian; DdB, Dogue de Bordeaux; ESS, English Springer Spaniel; FT, Fox Terrier; FB, French Bulldog; GP(u), German Pointer; GSD, German Shepherd Dog; GR, Golden Retriever; GD, Great Dane; Gr(u), Greyhound (Unspecified); HV, Hungarian Vizsla; Hu, Husky; JRT, Jack Russell Terrier; La, Labradoodle; LR, Labrador Retriever; Lu, Lurcher; Ma(u), Mastiff (Unspecified); Pi(u), Pinscher (Unspecified); Po(u), Poodle (Unspecified); RR, Rhodesian Ridgeback; Ro, Rottweiler; ST, Scottish Terrier; SBT, Staffordshire Bull Terrier; SP, Standard Poodle; TT, Tibetan Terrier; We, Weimaraner; WHWT, West Highland White Terrier; Wh, Whippet (from Dog breeds and body conformations with predisposition to osteosarcoma in the UK: a case-control study. Grace L Edmunds, Matthew J Smalley, Sam Beck, Rachel J Errington, Sara Gould, Helen Winter, Dave C Brodbelt, Dan G O'Neill. Canine Med Genetics, 2021, 8(1):2).

We have also identified breeds at higher risk of mammary cancer (Varney et al, Veterinary Record, 2023) as well as discovering that breed not only affects risk of getting cancer but also how that cancer may behave, at least for mammary tumours (Edmunds et al, Journal of Mammary Gland Biology and Neoplasia, 2023). Building on our previous work on c-KIT, we are now studying whether inheriting breed-specific haplotypes of the KIT gene underlies the well-known breed predispositions to canine mast cell tumours, a tumour type driven by aberrant activation of c-KIT signalling.

Our current focus has also provided opportunities to work with clinical colleagues to identify and validate potential new prognostic and predictive markers in a range of tumour types from companion animals.

Current grant support

• Breast Cancer Now (2023-2026) - Targeting long term responses to chemotherapy through a novel stem/immune vulnerability in Triple Negative Breast Cancer (co-applicant with Prof Richard Clarkson)

Collaborators

• Prof Richard Clarkson (Cardiff University)
• Dr Grace Edmunds (Bristol Veterinary School, Bristol University)
• Dr Melanie Dobromylskyj (Finn Pathologists)
• Dr Sam Beck (Independent Anatomic Ltd)
• Dr Anita Grigoriadis (Kings College London)
• Professor David Brodbelt (Royal Veterinary College)
• Dr Dan O'Neill (Royal Veterinary College)

Teaching

Personal tutor for Biomedical Science Undergraduates (1st - 4th year)

Project Supervisor for 3rd Year Undergradute Final Year Projects

Project Supervisor for Integrated Masters and Masters of Research Students

PhD Supervisor

Lecturer - Cell Biology (2nd Year Module)

Lecturer - Contemporary Topics in Disease (3rd Year Module)

Lecturer - Cancer: Cellular and Molecular Mechanisms and Therapeutics (3rd Year Module)

Biography

I carried out my PhD research and early postdoctoral training at the Institute of Cancer Research, at both the Sutton and Chelsea sites, working on mammary developmental biology. Following a one year EMBO Fellowship at the Netherlands Cancer Institute working with Prof Anton Berns and Prof Jos Jonkers on genetically modified mouse cancer models, I returned to the ICR as a senior postdoctoral fellow and then a junior group leader. At that time I began my research programme into using mouse models to understand the molecular and (stem) cellular origins of breast cancer heterogeneity, and using that knowledge to identify breast cancer subtype-specific molecular therapeutic targets. I moved to Cardiff School of Biosciences in 2012 as a Senior Lecturer with the new European Cancer Stem Cell Research Institute (ECSCRI). I was promoted to Reader and Deputy Director and then made a Professor in 2017. I was Director of ECSCRI from 2018 - 2022. I currently work on understanding the genetic drivers of cancer predisposition using veterinary clinical samples as model systems as well as developing new prognostic and predictive diagnostic approaches for veterinary molecular pathology.

Professional memberships

Member of the British Society for Veterinary Pathology

Academic positions

Present and previous appointments

2018 – 2022                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 – 2022                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.

Committees and reviewing

Co-organiser of 2017, 2018 and 2020 EMBO Workshops on Mammary Gland Biology (held at EMBL Heidelberg)

Founder member of the European Network of Breast Development and Cancer Laboratories (http://www.enbdc.org/)

Member of Breast Cancer Campaign/Breast Cancer Now Scientific Advisory Board (May 2012 – June 2017)

Co-Chair of BIOSI Athena SWAN Self-Assessment Team (to April 2016; lead author on application which achieved Athena SWAN Silver Award).

SWAN representative on the BIOSI Staff and Working Environment Committee (to April 2016)

ECSCRI representative on BIOSI safety committee (to January 2016)

Joint academic lead in the Cardiff Stem Cell Network (to January 2016)

BIOSI representative on the College of Biological and Life Sciences Animal Welfare and Regulated Procedures Committee (to January 2016)

Member of the Editorial Board of Breast Cancer Research (March 2015 – ongoing)

Member of Irish Health Research Board – Patient Oriented Panel (June 2013)

Member of the Editorial Board of the Journal of Mammary Gland Biology and Neoplasia (May 2011 - ongoing).

Deputy Group Leader of Group 7 (Invasion, Metastasis, Angiogenesis, Hypoxia, Stem Cells, Circulating Cells) of 2012 Breast Cancer Campaign Gap Analysis, October 2012.

Invited participant (Biology – Initiation of Breast Cancer specialist workshop), Breast Cancer Campaign gap analysis meeting, 2 November 2006 (Published as A. Thompson, K. Brennan, A. Cox, J. Gee, D. Harcourt, A. Harris, M. Harvie, I. Holen, A. Howell, R. Nicholson, M. Steel and C. Streuli on behalf of Breast Cancer Campaign Gap Analysis Meeting, 2 November 2006, London, UK (2008). Evaluation of the current knowledge limitations in breast cancer research: a gap analysis. Breast Cancer Research 10:R36).

Manuscript reviewer for Breast Cancer Research, Cancer Research, Carcinogenesis, Cell Stem Cell, Clinical and Experimental Metastasis, Expert Reviews in Molecular Medicine, Genes and Development, International Journal of Cancer, Journal of Cell Science, Nature, Nature Reviews Cancer, Oncogene and Stem Cells

Supervisions

I am not currently available to supervise new PhD students.