Polymerase-mediated ultramutagenesis and carcinogenesis in mice

项目总结/摘要 基因工程小鼠模型（GEMM）是研究癌症的重要工具。然而，在这方面， 越来越多的人关注GEMM不能概括人类癌症的突变负荷。GEMM 它们的总体突变率低得惊人，远低于在人类中观察到的水平。这使得 这些模型可用于致癌信号通路的研究，但极大地限制了它们用于研究 遗传异质性和克隆变异、肿瘤免疫学或突变负荷/碱基的影响 替代率对肿瘤行为和治疗反应的影响。后者已变得特别相关， 免疫检查点疗法的出现，考虑到治疗成功的最佳预测因素是高 体细胞突变的发生率，与肿瘤类型无关。同样的限制也可能会遇到 基于更新的基因组编辑方法的GEMM，指出需要替代方法， 我们现在知道，突变负荷定义了肿瘤生物学、临床 行为和治疗反应。 在本项目中，提交了对PAR-17-245“提高 哺乳动物模型的转化研究”，我们建议产生和表征第一个小鼠 基于聚合酶驱动的超突变的癌症模型。这些方法将1）促进任何模型的建模 由POLE超诱变驱动的癌症和2）允许任何GEMM在以下方面的有效“人源化”： 突变负荷我们的方法代表了一种新的和广泛适用的路线，以建立小鼠模型 它概括了人类癌症固有的突变负荷。这些新的遗传工具和 他们将使动物模型将刺激广泛的转化和临床前研究， GEMM以前并不适合，因此实现了PAR-17-245的目标。

PROJECT SUMMARY/ABSTRACT Genetically-engineered mouse models (GEMMs) are essential tools for the study of cancer. However, there is growing concern that GEMMs fail to recapitulate the mutation burden of human carcinomas. GEMMs have startlingly low overall mutation rates, far below what is observed in their human counterparts. This makes such models useful for studies of oncogenic signaling pathways, but greatly restricts their utility for studies of genetic heterogeneity and clonal variation, tumor immunology, or the impact of mutational load/base substitution rates on tumor behavior and response to therapy. The latter has become particularly relevant with the advent of immune checkpoint therapies, given that the best predictor of treatment success is a high incidence of somatic mutations, irrespective of tumor type. The same limitations are likely to be encountered with GEMMs based on newer genome-editing methods, pointing to the need for alternative approaches to optimize with respect to mutational load, which we now know defines so many aspects of tumor biology, clinical behavior and treatment response. In this project, submitted in response to PAR-17-245 “Research Projects to Enhance Applicability of Mammalian Models for Translational Research”, we propose to generate and characterize the first mouse cancer models based on polymerase-driven ultramutation. These approaches will 1) catalyze modelling of any cancer driven by POLE ultramutagenesis and 2) permit efficient “humanization” of any GEMM with respect to mutational load. Our approach represents a new and widely-applicable route to the creation of mouse models that recapitulate the mutational loads inherent to human cancer. These new genetic tools and the diverse animal models they will enable will stimulate a wide range of translational and preclinical investigations for which GEMMs were previously not well-suited, thus fulfilling the goals of PAR-17-245.