Dysregulation of intestinal morphogen gradients leads to ectopic stem-cell properties in intestinal neoplasia and inflammation/restitution

The human gut is made up of units called crypts, in which all cell types within it are derived from the stem cells housed at the crypt base. Control of these stem cells is thought to occur from the action of chemical messages secreted by cells that surround the stem cell. Derangement of these messages can lead to abnormal stem-cell growth leading to colorectal cancer formation which affects 39,000 people a year in the UK and is responsible for more than 16,000 deaths annually.

Intestinal inflammation is common, with inflammatory bowel disease affecting up to 2% of the population. Longstanding (chronic) intestinal inflammation and repair is a significant risk factor for cancer development. We hypothesise that inherited or sporadic genetic mutations and chronic intestinal inflammation and repair can dysregulate the delicately balanced chemical messages that control the stem-cell and that this disruption can lead to loss of control of stem-cell division, initiating tumour formation.

A team of clinicians and scientists intend to examine these functional mechanisms using biological models to mimic the changes seen in early tumourigenesis and in intestinal damage and repair. We believe that this work will lead to a better understanding of tumour development and growth, help to determine whether measurement of pathway disruption may predict patients' risk of cancer development and highlight potential target areas for anti-cancer treatment.

Aims and objectives: To assess the consequences of disrupted morphogen gradients in the intestinal epithelium and the consequences of this disruption on stem-cell dynamics. To do this we will test the following hypotheses:

1. That genetic disruption of tissue-specific GREM1 expression causes ectopic stem-cell properties resulting in ectopic crypt formation in human familial and sporadic polyps and an existing mouse model.
2. That the uniform media morphogen supplementation in intestinal organoid culture systems disrupts endogenous morphogen gradients promoting crypt budding.
3. That the dysregulated morphogen balance that results from an altered cellular context in intestinal inflammation and regeneration promotes crypt budding and fission as part of the intestinal repair process.

Methodology: Hypotheses are generated on the back of observations made in human tissue. We will then use state of the art in vitro culture systems and animal models to functionally test these hypotheses. All animal models are currently available at the host institute thus there is no requirement for time consuming transgenic animal generation.

Exploitation: Little is understood about the development of serrated polyp- and colitis- associated carcinogenesis. An understanding of the stem-cell dynamics that underlie these conditions will help understand tumour pathogenesis, aid in the development of biomarkers and may provide insight into genetic heterogeneity and response to therapy. Functional insight into morphogen signalling also remains an area of significant therapeutic interest as potentially druggable targets may harness the considerable biological effects of manipulation of these pathways in established tumours.

Benefit to myself and similar researchers:
I would obtain valuable generic and specific research skills - both to apply practically to the project in hand and to use in the future. I also hope to create links with academics and clinicians globally to help with the project and to contribute to others' research.

Benefit to the laboratory:
The Wellcome Trust laboratory group within which I will be working will directly benefit from the work and build on the results.

Impact on the wider public:
Only by investigating the functional mechanisms that underlie the pathogenesis of intestinal tumours can we hope to identify molecular intermediate phenotypes and develop effective biomarkers that can predict a patient's risk of future tumour development. The use of drugs such as Cetuximab to target dysregulated signaling pathways in colorectal cancer highlights the potential of therapeutically manipulating morphogenetic signalling pathways in colorectal cancer treatment. This proposal aims to identify potential drug targets and investigate how such therapies might have their effect. Furthermore, by addressing the pathogenesis of non-conventional colorectal cancer development I hope to be able to contribute to the debate on the correct surveillance of these lesions which could affect public services by changing current surveillance intervals for colonoscopy and indications for colectomy.

Benefit to the commercial sector:
If I consolidate results on aberrant gene expression in colorectal carcinogenesis in polyposis syndromes, groups including those from the commercial sector could work on potentially druggable targets. Any potential intellectual property will be discussed with Isis Innovations, a world leading technology transfer company.

Timescale:
The realistic timescale for the different aspects for my project is three years, and it is likely that subsequent work will take several years before changes are implemented in health services.