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.

项目摘要/摘要 遗传工程的小鼠模型（GEMM）是研究癌症的重要工具。然而， 人们越来越担心宝石无法概括人类癌的突变燃烧。宝石 从开始的总体突变率开始较低，远低于人类对应物中观察到的。这使得 这样的模型可用于研究致癌信号通路，但极大地限制了它们用于研究的效用 遗传异质性和克隆变异，肿瘤免疫学或突变载荷/碱的影响 肿瘤行为的替代率和对治疗的反应。后来与 鉴于治疗成功的最佳预测指标是一个很高的，免疫检查点疗法的冒险 体细胞突变的发生率，无论肿瘤类型如何。可能会遇到相同的限制 使用基于新的基因组编辑方法的GEMM，指出需要替代方法 在突变负荷方面进行优化，我们现在知道这定义了肿瘤生物学的许多方面 行为和治疗反应。 在该项目中，根据Par-17-245提交的“研究项目，以提高 用于翻译研究的哺乳动物模型”，我们建议生成和表征第一个鼠标 基于聚合酶驱动的超显着的癌症模型。这些方法将1）催化任何 由极极性充电和2）允许任何宝石的癌症 突变负荷。我们的方法代表了鼠标创建的新的广泛途径 这概括了突变负荷继承了人类癌症。这些新的遗传工具和潜水员 他们将启用的动物模型将刺激广泛的转化和临床前研究 以前哪个宝石不适合，因此实现了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