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

为了降低肠癌发病率和提高存活率，我们需要了解肿瘤发生的机制，以及它们如何影响对传统治疗的反应。BCL-3(因炎症等环境因素而增加)在实体肿瘤中是一个重要的致癌因子，尽管其作用机制尚不清楚。基于令人兴奋的新观察，我们认为bcl3是结直肠肿瘤细胞中干细胞样表型的驱动因子，促进肿瘤进展和治疗耐药。由于最近的报告强调了直接靶向癌症干细胞的局限性，我们相信识别和靶向干细胞可塑性的驱动因素作为新的治疗靶点具有巨大的潜力。结直肠癌仍然是英国第三常见的癌症，五年生存率为57%(2013年)。手术切除早期疾病仍然是唯一的根治方法，化疗用于治疗晚期疾病，但可悲的是，大多数患者将复发。我们必须更好地了解结直肠肿瘤发生的早期阶段，这样我们才能制定阻止肿瘤进展的策略，从而增加根治性手术的可能性，同时降低癌症发病率。重要的是，支持肿瘤进展的机制也可能导致晚期结直肠癌对目前的化疗方案产生抗药性。Wnt信号的失控被认为是结直肠癌的关键启动事件；Wnt/β-catenin信号的激活导致良性息肉或腺瘤的形成，这些息肉或腺瘤可以发展为完全癌。最近干细胞生物学的研究已经开始确定支持突变干细胞扩张的机制，这些突变干细胞有助于结直肠肿瘤发展的早期阶段，并可能成为治疗干预的新靶点。一个例子是核因子-kappaB途径，它已经被证明可以增强Wnt的激活，并诱导去分化导致非干细胞获得肿瘤启动能力。然而，靶向核因子-kappaB信号仍然具有挑战性，因为它在许多生理过程中发挥作用(包括先天性和获得性免疫反应)，需要一种更有针对性的方法。因此，我们发现BCL-3(核因子-kappaB信号的关键调节因子)增加了APC突变细胞中β-连环蛋白的转录活性，促进了结直肠癌细胞在体外的存活和干细胞样潜能以及肿瘤的活体生长。我们的研究计划旨在了解BCL-3在结直肠癌发生中的作用，以及如何最好地利用这一知识来管理这种疾病。我们将使用小鼠模型来确定靶向bcl3是否抑制肠道肿瘤的发生；这种方法使我们能够解决bcl3表达在结肠炎和散发性结直肠癌中的作用。我们将研究bcl3促进Wnt/β-catenin信号失控的细胞生长的机制，并确定bcl3/beta-catenin复合体的新转录靶点。最后，利用细胞生物学和流行病学相结合的方法，我们将确定所确定的bcl3/β-catenin靶点是否与结直肠癌风险和/或对传统治疗的反应有关。这一建议将为结直肠癌发生的早期生物学带来重要的新知识。它将确定bcl3在促进结直肠肿瘤发生的最早事件中的作用；确定bcl3/β-连环蛋白复合体作为结直肠肿瘤发生的潜在标记和预防目标。此外，它还将确定提高结直肠癌治疗效果的新靶点，并考虑到Wnt/β-catenin和bcl3/nf-kappaB信号在肿瘤发生中的重要性，可能对其他常见癌症具有更广泛的影响。

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.