Leedham Group: Gastrointestinal Stem Cell Biology Laboratory

01865 287518

Gastrointestinal Stem Cell Biology Laboratory: Bone Morphogenetic Protein signaling and stromal-epithelial interaction in intestinal inflammation and carcinogenesis

Over the last 30 years, rapid progress in colorectal cancer (CRC) genetics has meant that the ability to detect and understand epithelial somatic mutation often takes centre stage in CRC research. However, remembering the evolutionary maxim: Phenotype = Genotype + Environment, we believe that the unequivocally important role of epithelial genetic mutation in carcinogenesis should be considered in a broader context, incorporating the influence of the intestinal environment. We propose an updated model where cancer phenotype is the result of variable, interacting combinations of both genetic and environmental pathogenic factors. We have divided genetic influence into genetic predisposition and somatic mutation, and environmental influence into epithelial cell-extrinsic (microenvironmental) and intrinsic (cell-of-origin) context. The arrows reflect considerable interaction and inter-dependence between individual influences.

Model proposing how genetic and environmental influences interact and variably contribute to cancer phenotype. The relative importance of these individual but interacting factors may vary between individual tumours. For example, tumours in Familial Adenomatous Polyposis are the consequence of inherited genetic predisposition and optimally selected epithelial somatic mutations. In contrast colitis-associated cancers are predominantly driven by a disrupted cell-extrinsic microenvironment. This variability in pathogenic influence in individual tumours contributes to colorectal cancer molecular and clinical heterogeneity.

The intestinal mucosa is a complex ecosystem and the epithelium has a dynamic and inter-dependent relationship with its microenvironment, especially with the underlying stroma. Secreted cell signaling networks are the effector pathways of inter-compartmental crosstalk and regulate epithelial cell fate determination. In response to microenvironmental pressures such as intestinal inflammation and wounding, transient perturbation of cell-signaling promotes epithelial stem cell expansion, cell proliferation and migration. This is part of the physiological response to injury and is required to effect epithelial restitution. However, failure of restoration of homeostatic control in chronic inflammation, or pathological disruption of signaling pathways can result in neoplasia initiation/progression.

***Inter-compartmental cell-signaling pathways in the colonic epithelium.*** *The Wnt and BMP pathways generate polarized, reciprocal gradients from the crypt base to luminal surface.*

Our research explores these concepts using disrupted Bone Morphogenetic Protein (BMP) signaling and its pleiotropic antagonist Gremlin1 as exemplars of the paradigm. Our previous work has shown that genetic predisposition influences BMP/Grem1 signaling and that this can affect the cell-of-origin of resultant tumours. Our work now focuses on the role of microenvironmental (stromal) cell signaling in wound repair and carcinogenesis and investigates whether epithelial somatic mutation spectra can be used translationally, to reflect variable underlying disease pathogenesis.

Our research aims to

i) Improve understanding of the link between intestinal inflammation, regeneration and cancer by assessing the hitherto undetermined role of key stromal-epithelial signaling pathways.

ii) Assess these pathways for potential new therapeutic targets, using novel experimental agents

iii) Identify molecular biomarkers to stratify patients for treatments biologically appropriate for underlying tumour pathogenesis