Prof Gareth Inman - Growth Factor Signalling and Squamous Cancers
Introduction
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.
Email
Lab Report
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
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 Scotland Institute
2018-present: Professor of Cell Signalling, School 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
2024
Derby SJ, Dutton L, Strathdee KE, Stevenson K, Koessinger A, Jackson M, Tian Y, Yu W, McLay K, Misquitta J, Alsharif S, Clarke CJ, Gilmour L, Thomason P, McGhee E, McGarrity-Cottrell CL, Vanderlinden A, Collis SJ, Rominyi O, Lemgruber L, Solecki G, Olson M, Winkler F, Carlin LM, Heiland DH, Inman GJ, Chalmers AJ, Norman JC, Carruthers R, Birch JL. Inhibition of ATR opposes glioblastoma invasion through disruption of cytoskeletal networks and integrin internalization via macropinocytosis. Neuro Oncol. 2024;26(4):625-639.
2023
Bailey P, Ridgway RA, Cammareri P, Treanor-Taylor M, Bailey UM, Schoenherr C, Bone M, Schreyer D, Purdie K, Thomson J, Rickaby W, Jackstadt R, Campbell AD, Dimonitsas E, Stratigos AJ, Arron ST, Wang J, Blyth K, Proby CM, Harwood CA, Sansom OJ, Leigh IM, Inman GJ. Driver gene combinations dictate cutaneous squamous cell carcinoma disease continuum progression. Nat Commun. 2023;14:5211.
Singh SP, Smyth DJ, Cunningham K, Mukundan A, Byeon C-H, Hinck CS, White MPJ, Ciancia C, Wosowska N, Sanders A, Jin R, Lilla S, Zanivan S, Schoenherr C, Inman G, Dinther Mv, Dijke Pt, Hinck AP, Maizels RM. The helminth TGF-β mimic TGM4 is a modular ligand that binds CD44, CD49d and TGF-β receptors to preferentially target myeloid cells. bioRxiv. 2023:2023.2011.2013.566701.
Wang J, Harwood CA, Bailey E, Bewicke-Copley F, Anene CA, Thomson J, Qamar MJ, Laban R, Nourse C, Schoenherr C, Treanor-Taylor M, Healy E, Lai C, Craig P, Moyes C, Rickaby W, Martin J, Proby C, Inman GJ, Leigh IM. Transcriptomic analysis of cutaneous squamous cell carcinoma reveals a multi-gene prognostic signature associated with metastasis. J Am Acad Dermatol. 2023;10.1016/j.jaad.2023.08.012.
Bone M, Inman GJ. Exon specific oncogenic function of the long non-coding RNA PVT1 in cutaneous squamous cell carcinoma, a promising potential therapeutic target. Br J Dermatol. 2023.
2022
Cosgarea I, McConnell AT, Ewen T, Tang D, Hill DS, Anagnostou M, Elias M, Ellis RA, Murray A, Spender LC, Giglio P, Gagliardi M, Greenwood A, Piacentini M, Inman GJ, Fimia G, Corazzari M, Armstrong JL, Lovat PE. Melanoma secretion of TGFβ-2 leads to loss of epidermal AMBRA1 threatening epidermal integrity and facilitating tumour ulceration. Br J Dermatol. 2022; 186:606-607
Flanagan DJ, Amirkhah R, Vincent DF, Gundaz N, Gentaz P, Cammareri P, McCooey AJ, McCorry AMB, Fisher NC, Davis HL, Ridgway RA, Lohuis J, Leach JDG, Jackstadt R, Gilroy K, Mariella E, Nixon C, Clark W, Hedley A, Markert EK, Strathdee D, Bartholin L, Redmond KL, Kerr EM, Longley DB, Ginty F, Cho S, Coleman HG, Loughrey MB, Bardelli A, Maughan TS, Campbell AD, Lawler M, Leedham SJ, Barry ST, Inman GJ, van Rheenen J, Dunne PD, Sansom OJ. Epithelial TGFβ engages growth-factor signalling to circumvent apoptosis and drive intestinal tumourigenesis with aggressive features. Nat Commun. 2022;13:7551.
Smith CDL, McMahon AD, Ross A, Inman GJ, Conway DI. Risk prediction models for head and neck cancer: A rapid review. Laryngoscope Investigative Otolaryngology. 2022;7:1893-1908
2021
Dayal JHS, Mason SM, Salas-Alanis JC, McGrath JA, Taylor RG, Mellerio JE, Blyth K, South AP, Inman GJ. Heterogeneous addiction to transforming growth factor-beta signalling in recessive dystrophic epidermolysis bullosa-associated cutaneous squamous cell carcinoma. Br J Dermatol. 2021;184:697-708.
Hollis RL, Stillie LJ, Hopkins S, Bartos C, Churchman M, Rye T, Nussey F, Fegan S, Nirsimloo R, Inman GJ, Herrington CS, Gourley C. Clinicopathological Determinants of Recurrence Risk and Survival in Mucinous Ovarian Carcinoma. Cancers (Basel). 2021 Nov 21;13(22):5839.
Leach JDG, Vlahov N, Tsantoulis P, Ridgway RA, Flanagan DJ, Gilroy K, Sphyris N, Vázquez EG, Vincent DF, Faller WJ, Hodder MC, Raven A, Fey S, Najumudeen AK, Strathdee D, Nixon C, Hughes M, Clark W, Shaw R, van Hooff SR, Huels DJ, Medema JP, Barry ST, Frame MC, Unciti-Broceta A, Leedham SJ, Inman GJ, Jackstadt R, Thompson BJ, Campbell AD, Tejpar S, Sansom OJ. Oncogenic BRAF, unrestrained by TGFβ-receptor signalling, drives right-sided colonic tumorigenesis. Nat Commun. 2021;12:3464.
Thomson J, Bewicke-Copley F, Anene CA, Gulati A, Nagano A, Purdie K, Inman GJ, Proby CM, Leigh IM, Harwood CA, Wang J. The Genomic Landscape of Actinic Keratosis. J Invest Dermatol. 2021;141(7):1664-1674.e1667.
Kumari A, Shonibare Z, Monavarian M, Arend RC, Lee NY, Inman GJ, Mythreye K. TGFβ signaling networks in ovarian cancer progression and plasticity. Clin Exp Metastasis. 2021;38:139-161.
2020
Birch JL, Coull BJ, Spender LC, Watt C, Willison A, Syed N, Chalmers AJ, Hossain-Ibrahim MK, Inman GJ. Multifaceted transforming growth factor-beta (TGFβ) signalling in glioblastoma. Cell Signal. 2020;72:109638.
Smith HG, Jamal K, Dayal JH, Tenev T, Kyula-Currie J, Guppy N, Gazinska P, Roulstone V, Liccardi G, Davies E, Roxanis I, Melcher AA, Hayes AJ, Inman GJ, Harrington KJ, Meier P. RIPK1-mediated immunogenic cell death promotes anti-tumour immunity against soft-tissue sarcoma. EMBO Mol Med. 2020; 12:e10979.
Wei Q, Holle A, Li J, Posa F, Biagioni F, Croci O, Benk AS, Young J, Noureddine F, Deng J, Zhang M, Inman GJ, Spatz JP, Campaner S, Cavalcanti-Adam EA. BMP-2 Signaling and Mechanotransduction Synergize to Drive Osteogenic Differentiation via YAP/TAZ. Adv Sci (Weinh). 2020;7(15):1902931.
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;20:3428
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.
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; 180: 1135-1149
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.
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.
