Polymerase epsilon-based mouse and derived organoid models of intestinal cancer

项目摘要/摘要 肠癌是第三种最常见的恶性肿瘤，也是男性和女性癌症相关死亡的原因 女人。不幸的是，最近我们对潜在的肠道生物学和癌症的了解取得了进展- 相关的途径并没有显著改善患者的预后。而众多的动物 已经建立了肠癌的模型，主要是基于β-连环蛋白途径的错误调节， 人类癌症的一些关键特征(特别是肿瘤突变负担)现在已被认为是肿瘤的关键 进展和治疗反应，还没有在动物模型中进行充分的建模或研究 肠癌。 最近，基因组测序工作导致发现了一种肠癌突变子表型 其中看家DNA聚合酶的校对结构域中的单个氨基酸替换 导致人类癌症中所描述的最高突变率(超突变)。 与人类癌症不同，转基因动物模型表现出非常低的突变率，限制了它们的 肿瘤内异质性和竞争、免疫反应和免疫检查点研究的实用价值 治疗，现在已知是人类肿瘤生物学的基本方面。我们建议克服这些问题 通过建立在1)在产生肠癌动物模型方面的良好记录来限制 肿瘤动物模型及其发展的新遗传工具2)特征明确的条件性PoleP286R 我们以前用来建立强大的子宫内膜癌模型的等位基因，以及3)基因组学方面的专业知识， 炎症、肠癌和肠道疾病的小鼠模型。这些模型不仅有用 要概括POL驱动的肠癌，也要使任何肠癌小鼠模型人性化 尊重突变的负担。本提案是针对PAR-20-131提出的，旨在扩大和改进 用于转译癌症研究的哺乳动物模型的发展。

PROJECT SUMMARY/ABSTRACT Intestinal cancer is the 3rd most common malignancy and cause of cancer-related deaths in both men and women. Unfortunately, recent advances in our understanding of the underlying intestinal biology and cancer- related pathways have not translated to significantly improved patient outcomes. While numerous animal models of intestinal cancer have been developed, mostly based on misregulation of the β-catenin pathway, some key features of human cancers (particularly tumor mutational burden) now known to be critical for tumor progression and therapy response, have not been adequately modelled or investigated in animal models of intestinal cancer. More recently, genome sequencing efforts led to the discovery of an intestinal cancer mutator phenotype where single amino acid substitutions within proofreading domains of the housekeeping DNA polymerases result in the highest mutation rates described in human cancers (ultramutation). Unlike human cancers, genetically-engineered animal models exhibit very low mutation rates, limiting their utility for studies of intratumoral heterogeneity and competition, immune responses, and immune checkpoint therapies, now known to be essential aspects of human tumor biology. We propose to overcome these limitations in intestinal cancer animal models by building upon 1) a strong track record in the generation of cancer animal models and novel genetic tools for their development 2) a well-characterized conditional PoleP286R allele that we previously used to develop a robust model of endometrial cancer and 3) expertise in genomics, inflammation, intestinal cancer, and mouse models of intestinal disease. These models will be useful not only to recapitulate POL-driven intestinal cancers, but also to humanize any intestinal cancer mouse model with respect to mutational burden. This proposal is submitted in response to PAR-20-131 to expand and improve the development of mammalian models for translational cancer research.