Investigating the function of the BCL-3/Beta-catenin complex in promoting intestinal tumorigenesis and acquisition of therapeutic resistance.

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To decrease bowel cancer incidence and improve survival, we need to understand the mechanisms that drive tumorigenesis and how they impact response to conventional therapies. BCL-3 (increased by environmental cues such as inflammation) is an important oncogenic player in solid tumours, although its mechanism of action remains unclear. Based on exciting novel observations, we propose that BCL-3 acts as a driver of the stem-cell like phenotype in colorectal tumour cells, promoting tumour progression and therapeutic resistance. As recent reports highlight the limitations of directly targeting cancer stem cells, we believe that identifying and targeting drivers of stem cell plasticity have significant potential as new therapeutic targets.Colorectal cancer remains the third most common cancer in the UK with a five-year survival rate of 57% (2013). Surgical resection of early stage disease remains the only curative therapy, chemotherapy is used to treat advanced disease, but sadly most patients will relapse. It is crucial that we better understand the early stages of colorectal tumorigenesis so that we can develop strategies that stop tumour progression, hence increasing the potential for curative surgery as well as reducing cancer incidence. Importantly, mechanisms that support tumour progression may also cause advanced colorectal cancers to become resistant to current chemotherapeutic regimens. Deregulation of Wnt signalling is recognised as the key initiating event in colorectal cancer; activation of Wnt/beta-catenin signalling leads to the formation of benign polyps or adenomas, which can progress to become full carcinomas. Recent studies in stem cell biology have begun to identify the mechanisms underpinning the expansion of the mutant stem cells that contribute to the earliest stages of colorectal tumour development, and which may represent novel targets for therapeutic intervention. An example is the NF-kappaB pathway which has been shown to enhance Wnt activation, and induce de-differentiation causing non-stem cells to acquire tumour-initiating capacity. However, targeting NF-kappaB signalling remains challenging because of its role in many physiological processes (including innate and adaptive immune responses) and a more focused approach is required. It is therefore of significant interest we discovered that BCL-3 (a key regulator of NF-kappaB signalling) increases the transcriptional activity of beta-catenin in APC mutant cells, promoting the survival and stem-like potential of the colorectal tumour cells in vitro and tumour growth in vivo.Our research plan is designed to understand the role of BCL-3 in colorectal carcinogenesis and how this knowledge can be best used for the management of this disease. We will use mouse models to determine whether targeting BCL-3 inhibits intestinal tumorigenesis; this approach allows us to address the role of BCL-3 expression in colitis vs sporadic colorectal cancer. We will investigate the mechanism by which BCL-3 promotes the outgrowth of cells with deregulated Wnt/beta-catenin signalling and identify novel transcriptional targets for the BCL-3/beta-catenin complex. Finally using a combined cell biology and epidemiology approach, we will determine whether the BCL-3/beta-catenin targets identified are related to colorectal cancer risk and/or response to conventional therapy.This proposal will bring important new knowledge of the early biology of colorectal tumorigenesis. It will establish the role of the BCL-3 in promoting the earliest events in colorectal tumorigenesis; identifying the BCL-3/beta-catenin complex as potential marker of and target for prevention in colorectal tumorigenesis. In addition, it will identify novel targets to improve therapeutic efficacy in colorectal cancer and given the significance of Wnt/beta-catenin and BCL-3/NF-kappaB signalling in tumorigenesis, could have wider implications for other prevalent cancers.