A novel murine model of squamous lung cancer

一种新型的鳞状肺癌小鼠模型

• 批准号: NC/S001204/1
• 负责人: Frank McCaughan
• 金额: $ 38.95万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=NC%2FS001204%2F1
• 关键词: novel; murine; model; squamous; lung

Squamous lung cancer (SQC) is a type of non-small cell lung cancer (NSCLC). There are currently no specific therapeutic agents licensed to treat SQC and outcomes for patients with advanced disease are very poor. There are some targeted therapeutics available for the other common type of NSCLC - lung adenocarcinoma (ADC) - and more is understood about the molecular events that drive it. Likewise, there are mouse models of lung adenocarcinoma available that have been very helpful in understanding its biology and that can have direct relevance to the clinical disease. A major advantage that mouse models have over human organoid approaches is that they can be used to understand the dynamic and complex relationship between the developing and progressing tumour and its microenvironment. There is an urgent clinical need to improve our approach to SQC and this could be helped enormously by a rational mouse model that can replicate the genetic and tissue microenvironment context in which the tumour develops. Efforts to date have had some successes but, unfortunately, they are of limited utility in terms of translational studies or testing potential therapeutic combinations.In order to address this unmet need we have developed a new way of making a mouse model of SQC. We use mouse cells from an animal's lung and expand them in tissue culture before manipulating them using laboratory techniques to recreate the genetic abnormalities seen in the human disease. We then inject these cells back into the lung of a genetically identical (inbred) mouse and these cells lead to SQC tumours.This protocol has a major impact on the mission of the 3Rs. One reason is that for the traditional genetic models of this disease many breedings are required to get the right combination of genes to develop the type of cancer. In this case the genes are manipulated in cells rather than in an animal, so the process uses markedly fewer mice and is technically facile. A second reason is that we deliver the cells to one part of the lung, so that the animals develop a local tumour without becoming overtly unwell. This should allow us to refine the protocol so that the overall impact on animal welfare is significantly lessened. Third, many of the existing models of SQC use toxins to generate SQC with potentially complex and serious side effects. In this proposal we do not seek to administer toxins to any mouse at any stage. Finally we aim to engineer these cells so that we can monitor disease and the impact of a treatment in a single animal. A further combined impact of these measures is a marked reduction in the cost of doing mouse experiments on SQC.We have demonstrated in pilot data that our approach generates early murine SQC lesions within 3 weeks and large invasive tumours at around 4 months in wild type immunocompetent animals. We aim to validate and reproduce our pilot data and demonstrate its direct relevance to the human disease. Further we will show that the model can be used efficiently to address key basic and translational issues: the necessity of a specific driving oncogene for the cancer cells to stay alive; the potential to use drugs to prevent squamous lung cancer development; and a demonstration that this model will have utility for studying how the tumour interacts with its microenvironment.We are excited at the possibilties of this project and are enthusiastic about communicating with the potential end-users of this approach in academic community and pharma to ensure that the model is widely used.

鳞状肺癌（SQC）是一种非小细胞肺癌（NSCLC）。目前尚无特定的治疗剂来治疗SQC，晚期疾病患者的结果很差。有一些靶向治疗方法可用于其他常见类型的NSCLC-肺腺癌（ADC），并且有关驱动它的分子事件的了解更多。同样，有一些可用的肺腺癌的小鼠模型有助于理解其生物学，并且可以直接与临床疾病有关。小鼠模型比人体器官方法具有的一个主要优点是，它们可用于了解发育和进展的肿瘤及其微环境之间的动态和复杂关系。紧急临床需要改善我们对SQC的方法，这可以通过理性小鼠模型极大地帮助，该模型可以复制肿瘤发展的遗传和组织微环境环境。迄今为止的努力取得了一些成功，但不幸的是，在翻译研究或测试潜在的治疗组合方面，它们的实用性有限。为了满足这种未满足的需求，我们开发了一种新的方法来制定SQC的鼠标模型。我们在动物的肺中使用小鼠细胞，并在组织培养中扩展它们，然后使用实验室技术操纵它们来重现人类疾病中看到的遗传异常。然后，我们将这些细胞注入遗传相同（近交）小鼠的肺中，这些细胞导致SQC肿瘤。该方案对3RS的任务有重大影响。原因之一是，对于这种疾病的传统遗传模型，需要许多繁殖才能获得基因的正确组合来发展癌症的类型。在这种情况下，这些基因是在细胞而不是在动物中操纵的，因此该过程使用明显较少的小鼠，并且在技术上很容易。第二个原因是我们将细胞运送到肺的一部分，因此动物会发展出局部肿瘤而不会明显不适。这应该使我们能够完善协议，以便对动物福利的总体影响大大减少。第三，许多现有的SQC模型都使用毒素生成具有潜在复杂和严重副作用的SQC。在此提案中，我们不寻求在任何阶段对任何鼠标施用毒素。最后，我们旨在设计这些细胞，以便我们可以监测单一动物中疾病和治疗的影响。这些措施的进一步综合影响是在SQC上进行小鼠实验的成本显着降低。我们在Pilot数据中证明了我们的方法在3周内在3周内生成早期的Murine SQC病变，而在野生型免疫能力动物的4个月中，大约4个月的大型浸润性肿瘤。我们旨在验证和复制我们的飞行员数据，并证明其与人类疾病的直接相关性。此外，我们将证明该模型可以有效地解决关键基本和翻译问题：需要特定驱动癌基因以使癌细胞保持生命的必要性；使用药物预防鳞状肺癌发展的潜力；并证明了该模型将具有研究肿瘤如何与其微环境相互作用的实用性。我们对该项目的可能性感到兴奋，并热衷于与学术界和药品中该方法的潜在最终用户进行交流以确保该模型被广泛使用。