Prof Gareth Inman - Growth Factor Signalling and Squamous Cancers


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.