Gareth Inman - Growth Factor Signalling and Squamous Cancers

Introduction

Inman Gareth April 2019

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 and 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.

In collaboration with Owen Sansom’s laboratory, we have previously shown that both TGFBR1 and TGFBR2 are frequently mutationally inactivated in human cutaneous squamous cell carcinoma (cSCC) and that combined deletion of TGFBR1 coupled with activation of the MAPK pathway is sufficient to drive rapid invasive cSCC formation from the Lgr5+ve hair follicle bulge stem cells in the mouse. This has led us into studies profiling the molecular landscape of human cSCC. Our recent whole exome sequencing studies have identified driver genes and pathways that are implicated in cSCC progression and we are currently building upon these observations using whole genome sequencing and RNAseq in collaboration with Peter Bailey (University of Glasgow) and Irene Leigh (QMUL). There are striking similarities in the molecular landscape of all squamous cancers, and we are determining the biological roles of the genes, pathways and processes underpinning tumour progression in cSCC, head and neck SCC and the 'squamous' subtype of pancreatic cancer using in vitro, ex vivo and in vivo pre-clinical models.

 

Lab Report

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Key Publications

Inman GJ, Wang J, Nagano A, Alexandrov LB, Purdie KJ, Taylor RG, Sherwood V, Thomson J, Hogan S, Spender LC, South AP, Stratton M, Chelala C, Harwood CA, Proby CM, Leigh IM. The genomic landscape of cutaneous SCC reveals drivers and a novel azathioprine associated mutational signature. Nat Commun. 2018; 9: 3667.

Cammareri P, Rose AM, Vincent DF, Wang J, Nagano A, Libertini S, Ridgway RA, Athineos D, Coates PJ, McHugh A, Pourreyron C, Dayal JH, Larsson J, Weidlich S, Spender LC, Sapkota GP, Purdie KJ, Proby CM, Harwood CA, Leigh IM, Clevers H, Barker N, Karlsson S, Pritchard C, Marais R, Chelala C, South AP, Sansom OJ, Inman GJ. Inactivation of TGFβ receptors in stem cells drives cutaneous squamous cell carcinoma. Nat Commun. 2016; 7: 12493. doi: 10.1038/ncomms12493

Hannigan A, Smith P, Kalna G, Lo Nigro C, Orange C, O'Brien DI, Shah R, Syed N, Spender LC, Herrera B, Thurlow JK, Lattanzio L, Monteverde M, Maurer ME, Buffa FM, Mann J, Chu DC, West CM, Patridge M, Oien KA, Cooper JA, Frame MC, Harris AL, Hiller L, Nicholson LJ, Gasco M, Crook T, Inman GJ. Epigenetic downregulation of human disabled homolog 2 switches TGF-beta from a tumor suppressor to a tumor promoter. J Clin Invest. 2010; 120: 2842-57.

Inman GJ, Nicolás FJ, Hill CS. Nucleocytoplasmic shuttling of Smads 2, 3, and 4 permits sensing of TGF-beta receptor activity. Mol Cell. 2002; 10: 283-94

Biography

Education and qualifications

1995: PhD, University of London (Ludwig Institute), Supervisor Paul Farrell
1990: BSc, Biology, University of York

Appointments

2018-present: Director of Research Strategy, CRUK Beatson Institute
2018-present: Professor of Cell Signalling, Institute of Cancer Sciences, University of Glasgow
2017-2018:  Professor of Cell Signalling, School of Medicine, University of Dundee
2010-2017: Reader, Division of Cancer Research, School of Medicine, University of Dundee
2003-2010: Junior Group Leader, CRUK Beatson Institute

Current committee membership

Advisory Board, Institute Curie, Orsay, Paris
Editorial Board, Scientific Reports, Experimental Dermatology
Deputy Chair, FASEB SRC TGFβ superfamily Signalling in Health and Disease

Honours and awards

Ian Stevenson Award for Excellence in Public Engagement (joint with Dr C Henderson and Dr G Smith), University of Dundee, 2016
1st Association for International Cancer Research Fellowship, 2003

Recent Publications

2019

Hassan S, Purdie KJ, Wang J, Harwood CA, Proby CM, Pourreyron C, Mladkova N, Nagano A, Dhayade S, Athineos D, Caley M, Mannella V, Blyth K, Inman GJ, Leigh IM. A Unique Panel of Patient-Derived Cutaneous Squamous Cell Carcinoma Cell Lines Provides a Preclinical Pathway for Therapeutic Testing. International journal of molecular sciences. 2019;20.

Spender LC, Ferguson GJ, Hughes GD, Davies BR, Goldberg FW, Herrera B, Taylor RG, Strathearn LS, Sansom OJ, Barry ST, Inman GJ. Preclinical Evaluation of AZ12601011 and AZ12799734, Inhibitors of Transforming Growth Factor βSuperfamily Type 1 Receptors. Mol Pharmacol. 2019; 95: 222-34. doi: 10.1124/mol.118.112946

2018

Badshah, II, Brown S, Weibel L, Rose A, Way B, Sebire N, Inman G, Harper J, Kinsler V, O'Shaughnessy R. Differential expression of secreted factors SOSTDC1 and ADAMTS8 cause pro-fibrotic changes in linear morphoea fibroblasts. Br J Dermatol 2018 Oct 26. [Epub ahead of print]

Inman GJ, Wang J, Nagano A, Alexandrov LB, Purdie KJ, Taylor RG, Sherwood V, Thomson J, Hogan S, Spender LC, South AP, Stratton M, Chelala C, Harwood CA, Proby CM, et al. The genomic landscape of cutaneous SCC reveals drivers and a novel azathioprine associated mutational signature. Nat Commun 2018; 9: 3667.

Purdie KJ, Proby CM, Rizvi H, Griffin H, Doorbar J, Sommerlad M, Feltkamp MC, der Meijden EV, Inman GJ, South AP, Leigh IM, Harwood CA. The Role of Human Papillomaviruses and Polyomaviruses in BRAF-Inhibitor Induced Cutaneous Squamous Cell Carcinoma and Benign Squamoproliferative Lesions. Front Microbiol 2018; 9: 1806.

Rose AM, Spender LC, Stephen C, Mitchell A, Rickaby W, Bray S, Evans AT, Dayal J, Purdie KJ, Harwood CA, Proby CM, Leigh IM, Coates PJ, Inman GJ. Reduced SMAD2/3 activation independently predicts increased depth of human cutaneous squamous cell carcinoma. Oncotarget 2018; 9: 14552-66.

Spender LC, Ferguson JG, Hughes GD, Davies BR, Goldberg FW, Herrera B, Taylor RG, Strathearn LS, Sansom OJ, Barry ST, Inman GJ. Preclinical evaluation of AZ12601011 and AZ12799734, inhibitors of transforming growth factor beta superfamily type 1 receptors. Mol Pharmacol 2018. 95: 222-34.

2017

Cammareri P, Vincent DF, Hodder MC, Ridgway RA, Murgia C, Nobis M, Campbell AD, Varga J, Huels DJ, Subramani C, Prescott KLH, Nixon C, Hedley A, Barry ST, Greten FR, Inman GJ, Sansom OJ. TGFβ pathway limits dedifferentiation following WNT and MAPK pathway activation to suppress intestinal tumourigenesis. Cell Death Differ. 2017; 24: 1681-93.

Hurst LA, Dunmore BJ, Long L, Crosby A, Al-Lamki R, Deighton J, Souhtwood M, Yang X, Nikolic MZ, Herrera B, Inman GJ, Bradley JR, Rana AA, Upton PD, Morrell NW. TNFα drives pulmonary arterial hypertension by suppressing BMP type-II receptor and altering NOTCH signalling. Nature Commun. 2017; 8: 14079

Phillips TJ, Scott H, Menassa DA, Bignell AL, Sood A, Morton JS, Akagi T, Azuma K, Rogers MF, Gilmore CE, Inman GJ, Grant S, Chung Y, Aljunaidy MM, Cooke CL, Steinkraus BR, Pocklington A, Logan A, Collett GP, Kemp H, Holmans PA, Murphy MP, Fulga TA, Coney AM, Akashi M, Davidge ST, Case CP. Treating the placenta to prevent adverse effects of gestational hypoxia on fetal brain development. Sci Rep. 2017; 7: 9079.

Rose, AM, Sansom OJ, Inman GJ. Loss of TGF-β signaling drives cSCC from skin stem cells - More evidence. Cell Cycle 2017; 16: 386-7.

Spender LC, Inman GJ. Targeting BRAF-mutant tumours with TGFBR1 inhibitors. Aging (Albany NY). 2017; 9: 5-6.

2016

Cammareri P, Rose AM, Vincent DF, Wang J, Nagano A, Libertini S, Ridgway RA, Athineos D, Coates PJ, McHugh A, Pourreyron C, Dayal JH, Larsson J, Weidlich S, Spender LC, Sapkota GP, Purdie KJ, Proby CM, Harwood CA, Leigh IM, Clevers H, Barker N, Karlsson S, Pritchard C, Marais R, Chelala C, South AP, Sansom OJ, Inman GJ. Inactivation of TGFβ receptors in stem cells drives cutaneous squamous cell carcinoma. Nature Commun. 2016; 7: 12493.

Harwood CA, Proby CM, Inman GJ, Leigh IM. The Promise of Genomics and the Development of Targeted Therapies for Cutaneous Squamous Cell Carcinoma. Acta Derm Venereol. 2016; 96: 3-16.

Languino LR, Singh A, Prisco M, Inman GJ, Luginbuhl A, Curry JM, South AP. Exosome-mediated transfer from the tumor microenvironment increases TGFβ signaling in squamous cell carcinoma. Am J Transl Res. 2016; 8: 2432-7.

Spender, LC, Ferguson, GJ, Liu, S, Cui, C, Girotti, MR, Sibbett, G, Higgs, EB, Shuttleworth, MK, Hamilton, T, Lorigan, P, Weller, M, Vincent, DF, Sansom, OJ, Frame, M, ten Dijke, P, Marais, R, Inman, GJ. Mutational activation of BRAF confers sensitivity to transforming growth factor beta inhibitors in human cancer cells. Oncotarget. 2016; 7: 81995-2012.

Spender, LC, Inman, GJ. Fatal attractions? Correlations of CXCL12-CXCR4-CXCR7 expression with disease progression in melanoma and Kaposi sarcoma. Br J Dermatol. 2016; 175: 1140-1.

2014

MacKay C, Carroll E, Ibrahim AFM, Garg A, Inman GJ, Hay RT, Alpi A. E3 ubiquitin ligase HOIP attenuates apoptotic cell death induced by cisplatin. Cancer Res. 2014; 74: 2246-57

Spender LC and Inman GJ. Developments in Burkitt’s Lymphoma: novel cooperations in oncogenic MYC signaling. Cancer Manag Res. 2014; 6: 27-38.

Lab Members

Inman lab 178 March 2019

Post-doc

Jasbani Dayal (DEBRA)

Clinical Research Fellow

Richard Taylor (CRUK Dundee Cancer Centre)

Research

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Seminars

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