The project will explore observations already made in the lab, and builds on work previously funded by us. This suggests that a certain gene, known as BCL-3, may be a useful marker for response to chemo and radiotherapy. The project will work with both 2 dimensional and 3 dimensional cell culture models.
The research team
The new student will be supervised by Professor Ann Williams at the School of Cellular and Molecular Medicine at the University of Bristol.
Why study BCL-3 in rectal cancer?
From their observations of BCL-3, the team consider that it could have a role in preventing the death of cancer cells when treated with chemo-radiotherapy. Their aim is to understand the mechanism by which the cells are protected from cell death.
They will use clinical samples and population based studies to see whether the interactions of related genes could explain why current treatments fails some individuals. This will enable doctors to better identify the individuals who will respond to chemo-radiotherapies and will ultimately improve the treatment of all patients diagnosed with rectal cancer.
Why is it important to study BCL-3 in rectal cancer?
Rectal cancer occurs in the lower bowel, just above the anus, the rectum. It is one of the most common forms of bowel cancer.
Currently patients diagnosed with rectal cancer will undergo chemo-radiotherapy before surgery with the aim of reducing the size of the tumour in order to make the surgery more effective. Responses to this vary widely, with up to 40% of people gaining no benefit at all from this therapy. This puts them through needless and aggressive treatment to no benefit and delays lifesaving surgery.
There is an urgent need to develop a better understanding of why some patients don’t respond so that they can be treated earlier and, ultimately, new treatments can be found for them.
Final Report Summary
Bowel cancer is the second most common cause of cancer-related death in the UK, with tumour recurrence being a major factor affecting long-term CRC patient survival. Importantly, the incidence of bowel cancer is increasing in younger people (20- 50-year-olds) who often aren’t diagnosed until the disease has spread; therefore, it is critical we find effective ways to both prevent and treat bowel cancer
Within the tumour there are cells known as cancer stem cells (CSCs) which are more resistant to therapy and can repopulate the tumour after treatment has stopped, leading to disease relapse. These cells therefore represent an important therapeutic target to overcome tumour recurrence, but their targetability is limited by cell plasticity: the ability of other tumour cells to gain stem-cell properties.
Previously, we proposed that the protein BCL-3 (first identified in B-cell lymphomas) is a driver of tumour cell plasticity, causing the cancer cells to become more stem-like and thus making the tumour more resistant to therapy. The aim of this project was to determine the mechanism by which BCL-3 promotes stem-cell plasticity to design better, more targeted treatments for bowel cancer.
Results from this study confirmed that inhibiting BCL-3 activity reduced the stem cell capacity of bowel cancer cells, identifying for the first time that loss of BCL-3 function changed tumour cell metabolism (the way in which a cell uses energy to carry out essential life functions). First published in the 1920’s, the Warburg effect describes the way cancer cells must reprogramme their metabolism to supply the increased demand for both energy and biosynthetic intermediates to support their high proliferative rate. The cancer cells become more reliant on oxidative phosphorylation (OXPHOS) to meet these needs, OXPHOS being important for the cancer stem cells. Experiments described here show that targeting BCL-3 reduced OXPHOS and not glycolysis, and suggest that BCL-3 promotes OXPHOS in the tumour cells, identifying a novel mechanism by which BCL-3 could be supporting the stem-like properties of the colorectal cancer cells. This is a significant finding because it exposes a potential metabolic vulnerability of the high BCL-3 expressing cells: we propose that inhibition of OXPHOS in BCL-3 high tumours could improve the effectiveness of conventional treatments and reduce the likelihood that the cancer will relapse after the completion of chemo-radiotherapy.
Impact of Bowel & Cancer Research funding
As well as scientific discovery, Bowel Research UK funding trained Penny Timms in state-of-the-art bioinformatics and research techniques, equipping her for a research career. Penny has submitted her PhD thesis entitled “Investigating the mechanistic role of BCL-3 in promoting stem cell plasticity in colorectal cancer”. Penny has been an exceptional student and will continue her scientific training, having been offered a position at the Ragon Institute, MIT and Harvard, USA, in January 2022. She is currently preparing a manuscript for publication. Other immediate beneficiaries are academic researchers: this project describes fundamental mechanisms; reagents will be available to the research community upon publication.