Signalling pathways in cancer
Division of Cancer Research
Jacqui Wood Cancer Centre
University of Dundee
James Arrott Drive
Ninewells Hospital And Medical School
+(44) 01382 383366
Gareth Inman graduated with first class honours from The University of York. He carried out his PhD studies on Epstein Barr virus in Professor Paul Farrell’s laboratory in the Ludwig Institute for Cancer Research in St Mary’s Hospital, London, before joining Professor Ed Ziff’s laboratory as an HHMI postdoctoral fellow in New York. Gareth then returned to the Ludwig Institute as a Wellcome Trust postdoctoral fellow and studied TGFβ signalling in human B cells in Professor Martin Allday’s lab. He then moved to Dr Caroline Hill’s lab at the Imperial Cancer Research Fund to study TGFβ signalling dynamics. Gareth set up his own lab investigating TGFβ signalling in cancer at The Beatson Institute for Cancer Research in Glasgow in 2003 following his award of the first AICR International Cancer Fellowship. Gareth took up his readership in Dundee in 2010. Work in his lab is supported by the AICR, Cancer Research UK, Tenovus Scotland, The Anonymous Trust and the Ninewells Cancer Campaign.
The transforming growth factor beta (TGFβ) superfamily comprises approximately forty related dimeric polypeptide cytokines including the bone morphogenetic proteins (BMPs), the growth and differentiation factors (GDFs), activin, nodal and the TGFβs (TGFβ1, TGFβ2, TGFβ3). These growth factors play fundamental roles during mammalian development and act as homeostatic factors in adult life regulating tissue repair, wound healing and the immune response. As well as having vital normal physiological functions these factors play pivotal roles in disease pathogenesis and the emerging importance of TGFβ and BMP signalling in cancer biology is the primary focus of our studies. Paradoxically TGFβ can act as both a tumour suppressor and a tumour promoter. The tumour suppressor activities of TGFβ are ascribed to its ability to act as a potent negative regulator of cell proliferation and survival. As tumours progress they frequently avoid the tumour suppressive activities of TGFβ and switch their response to this cytokine and utilise it as a promoter of motility, survival, invasion, vascularisation, metastasis and immunosuppression. We have three fundamental questions that we are trying to answer in the laboratory using both in vitro cell biological and in vivo techniques coupled with analysis of primary patient tumour material:-
1) How do TGFβ/BMP act as tumour suppressors and how do tumour cells avoid this?
2) How do TGFβ/BMP act on tumour cells to promote cancer progression?
3) When and where do these events occur?
Our ultimate goals are to develop therapeutics that selectively target the pro-oncogenic actions of these cytokines and to identify patient selection criteria for their deployment.
Mechanisms of TGFβ/BMP mediated tumour suppression
The tumour suppressor activities of TGFβ are attributed to its ability to act as a potent cytostatic factor and inducer of apoptosis. We are studying TGFβ signalling in both normal primary human B cells and in model Burkitt’s Lymphoma (BL) cell lines. Our detailed molecular analyses in both normal germinal centre B cells and BL cell lines has revealed that TGFβ signalling acts as a central regulator of centroblastic B cell apoptosis (Spender et al., 2009) via co-ordinated regulation of the BCL2 family of cell death and survival proteins. Based upon these studies and those of others we are investigating the potential of targeting survival pathway signalling as a therapeutic target in B cell malignancies (Spender and Inman, 2009a) and have discovered that dual targeting of the pro-survival BCL2 family and the PI3K/mTOR pathway may be a valuable approach for lymphoma management (Spender and Inman, 2012). We have also revealed novel pathways of cytostasis in B cells (Spender and Inman, 2009b).
Our current studies are focusing on how TGFβ may act as a tumour suppressor in skin stem cells and how BMP9 may negatively regulate ovarian cancer cell proliferation in a context dependent fashion.
Switching TGFβ from a tumour suppressor to a tumour promoter.
The tumour cell autonomous switch of TGFβ responses from inhibition of proliferation and survival to promotion of growth, motility and invasion must involve genetic and epigenetic changes in the tumour cell genome (Inman, 2011). We have identified the first epigenetic change capable of simulataneously abrogating the cytostatic effects of TGFβ whilst enabling TGFβ to promote proliferation and motility (Hannigan et al., 2010). We have found that promoter methylation of the DAB2 gene in head and neck squamous cell carcinoma (HNSCC) correlates with the development of metastatic disease and a poor patient prognosis. In HNSCC cell lines expression levels of this gene dictate the TGFβ response. Re-expression of this gene restores TGFβ mediated growth arrest whilst knockdown of this gene abrogates this response. We have also found that this gene is downregulated in breast cancer and may predict site specific metastasis. We are now determining the role of this gene during tumourigenesis in-vivo using genetic and xenograft approaches. Excitingly, using comparative microarray analysis we believe we have identified TGFβ driven pro-proliferative and pro-invasion gene signatures. We are now undertaking a detailed mechansistic and clinical evaluation of the role and regulation of these genes which we hope will provide important new insight into mechanisms of tumour progression in both SCC and breast cancer.
BMP signalling in cancer.
Recent mutation and expression studies have implicated aberrant BMP signalling as potentially playing both tumour suppressive and tumour promotive roles in human malignancy. We have developed a sensitive bioassay for measuring multiple BMPs present in biological fluids to assess autocrine production of these cytokines by tumour cell lines and potentially their presence in patient serum samples (Herrera and Inman, 2009). Strickingly we have used this assay to determine that both bovine and human serum contain physiologically relevant concentrations of BMPs, an observation that not only indicates that these factors circulate but which may also have profound implications for cell culture experiments.
BMPs act as central regulators of ovarian physiology and may be involved in ovarian cancer development. We have characterised the expression of BMP receptors and Smads in immortalised ovarian surface epithelial cells (IOSE) and a panel of ovarian cancer cell lines. Using siRNA, ligand trap, inhibitor and ligand stimulation approaches we have found that BMP9 acts as a proliferative factor for IOSE and ovarian cancer cell lines (Figure 1B), signalling predominantly via an ALK2/Smad1/Smad4 pathway (Herrera et al., 2009). Using our bioassay we have found that some ovarian cancer cell lines have gained autocrine BMP9 signalling and we have gone on to show that this is required for proliferation. Furthermore, using immunohistochemistry analysis of an ovarian cancer tissue microarray we have found that 25% of epithelial ovarian cancers express BMP9 whereas normal human OSE specimens do not. We are now seeking to understand how and when BMP9 drives cancer cell proliferation and to evaluate the potential of targeting ALK2 as a cancer therapeutic.
- Recent Publications from the Inman Lab:-
- Mackay C, Carroll E, Ibrahim AF, Garg A, Inman GJ, Hay RT, Alpi AF. E3 Ubiquitin Ligase HOIP Attenuates Apoptotic Cell Death Induced by Cisplatin. Cancer Res. 2014 Apr 15;74(8):2246-57. doi: 10.1158/0008-5472.CAN-13-2131. Epub 2014 Mar 31.
- Spender LC, Inman GJ. Developments in Burkitt's lymphoma: novel cooperations in oncogenic MYC signalling. Cancer Manag Res. 2014 Jan 9;6:27-38. eCollection 2014. Review.
- Acosta JC, Banito A, Wuestefeld T, Georgilis A, Janich P, Morton JP, Athineos D, Kang TW, Lasitschka F, Andrulis M, Pascual G, Morris KJ, Khan S, Jin H, Dharmalingam G, Snijders AP, Carroll T, Capper D, Pritchard C, Inman GJ, Longerich T, Sansom OJ, Benitah SA, Zender L, Gil J. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat Cell Biol. 2013 Aug;15(8):978-90. doi: 10.1038/ncb2784. Epub 2013 Jun 16.
- Wang, H; McHugh, A; Matin, R; Fleming, C; Leigh, I; Inman, G; Crook, T; Proby, C; A two gene serum epigenetic signature detects metastatic melanoma with high sensitivity and specificity; Journal of Investigative Dematology; 2013 May; 133(1); S235*S235
- Herrera B; Garcia-Alvaro M, Cruz S, Walsh P, Fernandez M, Roncero C, Fabrgeta I, Sanchez A, Inman GJ. (2013) BMP9 is a proliferative and survival factor for human hepatocellular carcinoma cells. Plos. One 8(7):e 69535.
- Spender, L.C, Carter, M.J., O’Brien, D.I., Clark, L.J., Yu, J., Michalak, E.M., Happo, L., Cragg, M.S., Inman, G.J. (2013) Transforming Growth Factor-β directly induces PUMA during the rapid induction of apoptosis in Myc-driven B-cell lymphomas. J. Biol. Chem. 288(7):5198-209.
- Elston, R. and Inman, G.J. (2012) Crosstalk between p53 and TGFβ signalling. Journal of Signal Transduction Article ID 358476.
- Spender, L.C. and Inman, G.J. (2012) Phosphoinositide-3-kinase/AKT/mTORC1/2 signalling determines sensitivity of Burkitt’s Lymphoma cells to BH3-mimetics. Mol Cancer Res. 10(3):347-59.
- Spender, L.C and Inman, G.J. (2011) Inhibition of Germinal Centre Apoptotic Programmes by Epstein-Barr Virus. Adv. Hematol. 2011:829525 Epub 2011 Oct 23.
- Inman, G.J. (2011) Switching TGFβ from a tumour suppressor to a tumour promoter. Curr Opin Genet Dev. 21(1): 93-99.
- Hannigan, A., Smith, P., Kalna,G., Lo Nigro, C., Orange, C., O’Brien, D., Shah, R., Syed,N., Spender, L.C., Herrera, B., Thurlow, J.K., Lattanzio, L., Monteverde, M., Maurer, M.E., Buffa, F.M., Mann, J., Chu, D.C., West, C.M.L., Patridge, M., Oien, K.A., Cooper, J.A., Frame, M.C., Harris, A.L., Nicholson, L.J., Gasco,M., Crook, T. and Inman, G.J.. (2010) Epigenetic downregulation of human disabled homolog 2 switches TGFβ from a tumour suppressor to a tumour promoter. Journal of Clinical Investigation 120(8):2842-57.
- Herrera, B., van Dinther, M., ten Dijke, P. and Inman, G.J. (2009) Autocrine Bone Morphogenetic Protein 9 signals via Activin Like Kinase 2/Smad1/Smad4 to promote ovarian cancer cell proliferation. Cancer Research 69(24):9524-62.
- Spender, L.C. and Inman G.J. (2009) Targeting the BCL2 family in germinal centre malignancies. Expert Opinion in Therapeutic Targets Dec; 13(12):1459-72.
- Herrera, B and Inman G.J. (2009) A rapid and sensitive bioassay for the Simultaneous measurement of multiple bone morphogenetic proteins. Identification and quantification of BMP4, BMP6 and BMP9 in bovine and Human serum. BMC Cell Biol. March 19.10:20.
- Spender, L.C. O’Brien, D.I., Simpson, D., Dutt, D., Gregory, C.D, Allday, M.J., Clark, L. and Inman, G.J. (2009) TGFβ induces apoptosis in human B cells via transcriptional regulation of BIK and BCL-XL. Cell Death Diff 16(4):593-602.
- Fleming Y.M., Ferguson, G.J., Spender, L.C., Larsson, J., Karlsson, S., Ozanne, B., Grosse, R. and Inman, G.J. (2009) TGFβ mediated activation of RhoA signalling is required for efficient V12HaRas and V600EBRaf transformation. Oncogene 28(7):983-93.
- Spender, L.C. and Inman, G.J. (2009) TGFβ induces growth arrest in Burkitt’s Lymphoma cells via transcriptional repression of E2F-1. J. Biol. Chem. 284(3):1435-42.
I am actively involved is aspects of the Cancer Biology MRes programme and supervise masters and PhD students and take part in the SSC Medical student undergraduate programme.
Peter Walsh 2011-2014
Alana Burns 2012-2015
Aidan Rose (clinical Fellow) 2012-2015
Lectures at international meetings:
FASEB Summer Research Conference, The TGFβ superfamily: Signaling in Development and Disease, Steam Boat Springs, USA, 2013
Tenovus Symposium, Glasgow, 2012.
A*STAR symposium, Singapore, 2012.
FASEB Summer Research Conference, The TGFβ superfamily: Signaling in Development and Disease, Lucca, Italy, 2011
8th International BMP congress, Leuven, Belgium, 2010.
Beatson International Cancer Conference, Glasgow, 2010.
BMP International workshop, Berlin, 2009.
Beatson International Cancer Conference, Glasgow, UK, 2009.
FASEB summer research conference. TGFβ Superfamily: Signaling in Development and Disease, Arizona, USA, 2009.
Keystone Symposia. TGFβ family in homeostasis and Disease, Santa Fe, NM, USA, 2008.
FASEB summer research conference: TGFβ superfamily: signaling and development. Tuscon, Arizona, USA, 2007.
Beatson International Cancer Conference. Glasgow, UK, 2007.
TGFβ and Cancer workshop, The Lighthouse, Glasgow, UK, 2006.
Scottish Transcription Meeting. University of Glasgow, UK, 2005.
Xth International Epstein-Barr-Virus Meeting, Yale, USA 2000.
LICR 25th Anniversary Symposium, Zurich, Switzerland, 1997.
External invited seminars.
St Bartholomew's Cancer Centre, London, 2013
CLS Research Sympsosium, University of Dundee, Crieff, 2013
Breakthrough Breast Cancer Research Centre, London, 2012
UCL Cancer Institute, London, 2012
Cancer Research Center, Lyon, France, 2012
Blizzard Institute, Queen Mary’s University of London, 2012
Belfast Cancer Centre/Queens Medical Centre, Belfast, 2011.
Ludwig Institute for Cancer Research, University of Oxford, 2011.
University of Southampton, 2011.
CRUK Senior Fellows’ meeting, Manchester, 2010.
University of Manchester, 2010.
Department of Pharmacology, University of Marburg, Germany, 2010.
University Of Bristol, 2009.
University of Dundee, 2009.
The Institute of Cancer Research, Barts and the London School of Medicine and Dentistry, London, 2009.
Edinburgh Cancer Research Centre, University of Edinburgh, 2009.
Genzyme Corp., Boston, MA, USA, 2008.
CRUK Institute for Cancer for Cancer Studies, Birmingham University, 2007.
Astra Zeneca, Alderley Park, UK, 2007.
Cancer Research UK Molecular Oncology Unit, Barts and The London School of Medicine and Dentistry, UK, 2007.
University of East Anglia, UK, 2005
Glasgow Caledonian University, UK, 2005.
Institute of Comparative Medicine University of Glasgow Veterinary School, UK, 2004.
Department of Molecular Pharmacology, University of Heidelberg, Germany, 2003.
Beatson Institute for Cancer Research, Glasgow, Scotland, 2002.
Ludwig Institute for Cancer Research seminar series, St Mary’s Hospital Medical School, London 2002.
Marie Curie Research Institute, Oxted, Surrey, 2002.
Almroth-Wright lecture series, St Mary’s Hospital Medical School, London, 2000.
St George’s Hospital Medical School, London, 1999.
Queen’s Medical Centre, University of Nottingham, Nottingham, 1999.
Dr Blanca Herrera: Assistant Professor, Departamento de Bioquimica y Biologia Molecular, Universidad Complutense de Madrid, Spain.
Dr G. John Ferguson: Babraham Institute, Cambridge, UK
Dr Darren O'Brien: Department of Haematology, Western General Infirmary, Edinburgh, UK
Dr Adele Hannigan: EnGeneIC Cancer Therapeutics, Sydney, Australia
Dr Yvonne Fleming: Teacher training, Glasgow, UK