Regenerative and oncogenic programmes for the therapeutic treatment of chronic liver fibrosis and liver cancer

The ideal candidate for this project within the Cellular and Molecular Biology Programme is a self-motivated student, seeking to gain both scientific and technical skills in the cancer biology field. The student will be co-supervised for the entire length of the project by a postdoctoral research associate and the PI (Professor Evan) and will acquire a variety of biological and molecular laboratory techniques including: immune-staining, microscopy, flow cytometry, histology, RT-qPCR and cell culture. A part of this project involves in vivo experiments, and full training and Home Office accreditation will be provided.

Furthermore, the student will be engaged in scientific discussions, critical thinking/data analysis, and will have the opportunity to gain scientific presentation skills by participation to international conferences. The student will be exposed to a stimulating and highly international lab environment composed of scientists from different backgrounds.


Project Description

Despite the fact that individual tumours harbour a bewildering array of genetic differences as a result of the random acquisition of mutations it is remarkable that tumours arising in the same tissue are very similar and different to tumours arising in other tissues. Moreover, the same oncogenic “driver” mutations can elicit phenotypically different tumours in different tissues. This suggests that the evolution of cancer is significantly restricted by its tissue of origin.

One attractive hypothesis is that pre-existing physiological programmes characteristic of a particular tissue are somehow engaged inappropriately during tumourigenesis by deregulated (oncogenic) signalling pathways. Wound healing and tissue regeneration are characterised by profound changes in cellular signalling and extensive crosstalk between epithelial, stromal and immune cell compartments. These physiological but not homeostatic events share a remarkable similarity with events that characterise the formation and development of many solid tumours arising in different tissues. One prediction of this hypothesis is that oncogenic properties results from the persistency/deregulation of physiologic programmes, otherwise finely regulated, without the need to invoke the acquisition of de-novo properties. For example, after injury cell expansion (regeneration) and resolution are tightly temporally regulated as intertwined but sequential phases. In cancers the regenerative phase persists and the “wound” fails to resolve. The similarities observed between the regenerative phase after tissue injury and cancer are not shared with the normal homeostatic turnover of tissues.

Our preliminary data in mice that allow rapid switching of Myc activity demonstrate that persistent Myc activity drives persistent regenerative phase following liver injury that is maintained as long as Myc is present. Loss of Myc activity rapidly precipitates the resolution phase. However, the resolved tissue after long-term Myc-dependent regeneration is abnormal and characterised by extensive fibrosis. In contrast, persistent physiological Myc activity has little effect in liver tissue in the absence of injury indicating the presence on a cooperating signal invoked by the injury.

Hypothesis:

Deregulated Myc “hacks” into the tissue-resident regenerative programme thus maintaining a cell expansion with its attendant stromal and immune cell alterations at the expense of tissue resolution.
We further predict that Myc engages a cytokine/chemokine code during both regeneration and tumourigenesis that is specific to a particular tissue. Our genetically engineered mice that allow rapid toggling of physiological Myc activity in different tissues provide a perfect model for elucidating the signals that regulate both the regenerative and the resolution phases and how these signals are subverted in tumourigenesis. It is possible that some of these signalling components will provide attractive therapeutic targets.

The specific aims of this project are:

1. Identify the cellular changes induced by Myc in the regenerative programme that sustain growth, and the effects of switching off Myc during different stages of liver regeneration.
2. Determine Myc’s role in stromal remodelling, with particular emphasis on the interplay between epithelial and immune cell recruitment during regeneration, resolution and tumourigenesis.
3. Validate the manipulation of Myc effectors for the therapeutic treatment of chronic liver fibrosis and liver cancer.