Polymerase-mediated ultramutagenesis and carcinogenesis in mice

聚合酶介导的小鼠超突变和致癌作用

• 批准号: 10548853
• 负责人: DIEGO H CASTRILLON
• 金额: $ 54.16万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10548853
• 关键词: Acceleration; Alleles; Amino Acid Substitution; Animal Cancer Model; Animal Model; Bacterial Artificial Chromosomes; Behavior; Biology; Breeding; Bypass; Cancer Model; Carcinoma; Cell division; Cells; Clinical; Community Clinical Oncology Program; Cre driver; Cytotoxic T-Lymphocytes; DNA Polymerase II; DNA Sequence Alteration; DNA biosynthesis; Development; Endometrial; Endometrial Carcinoma; Exhibits; Female; Frequencies; Generations; Genetic; Genetic Engineering; Genetic Heterogeneity; Genetic study; Genetically Engineered Mouse; Genomics; Goals; Growth; Hematopoietic Neoplasms; Hereditary Nonpolyposis Colorectal Neoplasms; Histologic; Housekeeping; Human; Immune response; Immunology; Incidence; Inflammatory; Inherited; Investigation; KRASG12D; Knock-in; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Methods; Mismatch Repair; Mismatch Repair Gene Inactivation; Modeling; Monitor; Mus; Mutation; Mutation Spectra; Normal Cell; Nose; Oncogenic; Outcome; Phenotype; Polymerase; Prediction of Response to Therapy; Process; Prognosis; Research Project Grants; Role; Route; Signal Pathway; Somatic Mutation; Survival Analysis; T cell infiltration; T-Lymphocyte; Tissues; Translational Research; Tumor Biology; Variant; anti-PD-L1 therapy; base; behavioral response; carcinogenesis; cell growth; cell mediated immune response; checkpoint therapy; exome; experimental study; gastrointestinal carcinoma; genome editing; genome sequencing; humanized mouse; immunological status; improved; interest; mouse model; neoantigens; novel; pre-clinical; response; sarcoma; success; tool; translational cancer research; translational model; treatment response; tumor; tumor behavior; tumor eradication; tumor heterogeneity; tumor immunology; tumor progression; whole genome

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.

项目概要/摘要 基因工程小鼠模型（GEMM）是研究癌症的重要工具。然而， 人们越来越担心 GEMM 无法重现人类癌症的突变负担。基因工程模型 总体突变率低得惊人，远低于在人类同类中观察到的水平。这使得 这些模型对于致癌信号通路的研究很有用，但极大地限制了它们在癌症研究中的实用性 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 鉴于治疗成功的最佳预测指标是免疫检查点疗法的出现 体细胞突变的发生率，与肿瘤类型无关。可能会遇到相同的限制 与基于更新的基因组编辑方法的 GEMM 一起，指出需要替代方法 针对突变负荷进行优化，我们现在知道突变负荷定义了肿瘤生物学、临床的许多方面 行为和治疗反应。 在此项目中，根据 PAR-17-245“增强适用性的研究项目”提交 用于转化研究的哺乳动物模型”，我们建议生成并表征第一只小鼠 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 POLE 超突变驱动的癌症和 2) 允许任何 GEMM 在以下方面进行有效的“人性化” 突变负荷。我们的方法代表了一种新的、广泛适用的小鼠模型创建途径 概括了人类癌症固有的突变负荷。这些新的遗传工具和多样化的 他们将启用的动物模型将刺激广泛的转化和临床前研究 GEMM 以前不太适合，从而实现了 PAR-17-245 的目标。

项目成果

The mismatch recognition protein MutSα promotes nascent strand degradation at stalled replication forks.

• DOI: 10.1073/pnas.2201738119
• 发表时间: 2022-10-04
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Zhang, Junqiu;Zhao, Xin;Liu, Lu;Li, Hao-Dong;Gu, Liya;Castrillon, Diego H.;Li, Guo-Min
• 通讯作者: Li, Guo-Min

Endometrial polyps are non-neoplastic but harbor epithelial mutations in endometrial cancer drivers at low allelic frequencies.

• DOI: 10.1038/s41379-022-01124-5
• 发表时间: 2022-11
• 期刊: MODERN PATHOLOGY
• 影响因子: 7.5
• 作者: Sahoo, Subhransu S.;Aguilar, Mitzi;Xu, Yan;Lucas, Elena;Miller, Valerie;Chen, Hao;Zheng, Wenxin;Cuevas, Ileana C.;Li, Hao-Dong;Hitrys, David;Wachsmann, Megan B.;Bishop, Justin A.;Cantarell, Brandi;Gagan, Jeffrey;Koduru, Prasad;SoRelle, Jeffrey A.;Castrillon, Diego H.
• 通讯作者: Castrillon, Diego H.

Histopathologic diagnosis of endometrial precancers: Updates and future directions.

• DOI: 10.1053/j.semdp.2021.12.001
• 发表时间: 2022-05
• 期刊: Seminars in diagnostic pathology
• 影响因子: 2.3