Epithelial cell dynamics during postnatal growth; relevance for oesophageal cancer development

This PhD position will offer the candidate the opportunity to conduct research in a cross-disciplinary research programme where quantitative methods will be exploited to study epithelial stem cell plasticity using postnatal in vivo models. The cell behaviour during normal tissue expansion after birth will be compared to the cellular changes leading to oesophageal carcinogenesis. The aim is to identify molecular targets governing epithelial cell responses during early tumour formation that can be used for cancer therapeutics and diagnostics.

Aim
Despite advances in the cancer field, we still know surprisingly little about how epithelial tumours originally form and the identity of cells with tumour initiating potential. Recent reports have shown the remarkable ability of epithelial cells to change their behaviour in response to tissue needs, with differentiating epithelial cells being able to reacquire stem cell-like behaviour during early tumour formation (1). This provides some clues as to why the cell of origin of cancer has proven so difficult to pin down so far. Understanding the factors that regulate cellular plasticity in the rapid growth of the oesophagus during postnatal development will provide insights into the long-term maintenance of the tissue, and the pathways leading to dysregulated growth and cancer.

This proposal will use a multidisciplinary approach to investigate the cellular and molecular mechanisms underlying stem cell behaviour in the oesophageal epithelium. The principles governing changes in cell dynamics and fate will be explored quantitatively during early postnatal growth, as a physiological model of regulated tissue expansion. Insights gained from the study of normal tissue growth during the early stages after birth will form a basis to explore factors leading to abnormal growth in the transition to oesophageal carcinogenesis.

The specific objectives are:

• Perform quantitative lineage tracing in epithelial and mesenchymal cell populations during postnatal oesophageal expansion.
• Define the changes in cell behaviour leading to the onset of homeostasis.
• Identify molecular regulators governing the developmental to homeostatic “switch” in epithelial cells.
• Use models of oesophageal tumorigenesis to unveil the clinical relevance of the uncovered mechanisms.

Background
Oesophageal cancer remains one of the least explored malignancies. However, in recent years, its increasing incidence and poor prognosis have stimulated interest from the cancer community to understand the pathways to the initiation and progression of the disease.

Evidence indicates that the aetiology of oesophageal adenocarcinoma involves significant changes in the epithelial cell program. Stratified epithelial cells tend to assume a more columnar identity during the early stages of the disease, consistent with a change in the cell fate behaviour of progenitors during early carcinogenesis. However, recent studies have shown that such plasticity is not limited to pathological conditions, but it is instead a common feature of epithelial cells to protect tissue integrity and that of the entire organism in response to perturbations (2, 3). Cell fate is, therefore, not as restricted as originally thought, with epithelial cells exhibiting a significant degree of plasticity and adaptability.

We have recently shown the remarkable ability of oesophageal epithelial cells to change their behaviour to restore homeostasis when challenged. Using in vivo quantitative lineage tracing we have shown that the progenitor cells that, under normal conditions, maintain the tissue, have the ability to redefine their cell fate program in order to restore tissue integrity when perturbed by injury or acquisition of advantageous mutations (4, 5).

Critical understanding of the cellular and molecular mechanisms controlling changes in cell fate decision will provide essential knowledge on the early responses during oesophageal carcinogenesis. To explore this question, it is first essential to understand the dynamic behaviour of oesophageal epithelial cells in a physiological context. During early postnatal development the mouse oesophagus must drastically expand in concert with the growth of the animal, providing a convenient model to study the regulation of epithelial cell dynamics outside homeostasis, and compare it with its uncontrolled counterpart in cancer. The outcome of this project will reveal not only fundamental questions about epithelial cell biology, but also the mechanisms restricting uncontrolled tissue expansion, providing potential targets for cancer therapies.

For full project details please to go www.cambridgecancercentre.org.uk/studentships