Visualizing tumor heterogeneity in an immune intact and autochthonous mouse model of breast cancer

可视化免疫完整和本地乳腺癌小鼠模型中的肿瘤异质性

• 批准号: 10348129
• 负责人: Joshua Clair Snyder
• 金额: $ 36.54万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-09 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10348129
• 关键词: Animals; Bar Codes; Basic Science; Biological Models; Breast Cancer Model; Breast Cancer Patient; Carcinoma; Cells; Clinic; Clinical effectiveness; Clonal Evolution; Clonality; Complex; Data; ERBB2 gene; Epithelial; Epithelial Cells; Evolution; Future; Genes; Genetic; Genetic Heterogeneity; Genetic Models; Growth; Heterogeneity; Human; Image; Immune; Immune system; Malignant Neoplasms; Mammary gland; Metastatic breast cancer; Modeling; Molecular; Mus; Neoplasm Metastasis; Oncogenes; Oncogenic; Outcome; Phenotype; Pre-Clinical Model; Property; Protein Isoforms; Protocols documentation; Public Health; Publishing; Recurrence; Reproducibility; Research Project Grants; Resistance; Resource Sharing; Resources; Somatic Mutation; Source; Standardization; Stromal Cells; System; Techniques; Testing; Therapeutic Uses; Time; Translating; Translational Research; Treatment Efficacy; Tumor Biology; Tumor Escape; Variant; Work; clinical predictors; diagnostic assay; efficacy research; fluorescence imaging; gastrointestinal epithelium; human disease; improved; malignant breast neoplasm; mouse model; multiplex diagnostics; novel; novel therapeutics; preclinical trial; standard of care; stem; therapy resistant; tool; transcriptomics; treatment response; tumor; tumor heterogeneity; tumor microenvironment

ABSTRACT Genetically modified mouse models of breast cancer have been used for decades as premier basic science tools for mechanistic discovery. However, the successful implementation of mouse models as surrogates of therapeutic efficacy and translational research has been challenging. One major challenge for status quo approaches is their limited ability to model the genetic heterogeneity observed in breast cancers. Metastatic and treatment resistant HER2+ breast cancers are incurable largely due to this heterogeneity, the source of which may stem from the competition and evolution of multiple oncogenic isoforms of the driver gene HER2. The objective for this proposal is to recapitulate the genetic heterogeneity of HER2 oncogenes in a genetically tractable model more closely resembling the human condition – including an intact immune system and stromal network. Published preliminary data recently described a Cancer rainbow (Crainbow) modeling system for fluorescently barcoding and expressing multiple tumor driver genes in a single immune intact mouse. The fluorescent barcode is retrieved by multispectral imaging and single-cell “omics” techniques providing a simple solution for inducing intratumor heterogeneity and visualizing its evolution. Any tumor driver gene can be incorporated into Crainbow mice. Therefore, this proposal will test the central hypothesis that modeling the oncogenic heterogeneity of HER2 in a Cancer rainbow mouse recapitulates the phenotypic heterogeneity found in treatment resistant and metastatic HER2+ breast cancers. The central hypothesis will be tested by completing four specific aims seeking to: (Aim 1) Validate a HER2 Crainbow mouse model of tumor heterogeneity, (Aim 2) Demonstrate heterogeneity within the tumor epithelium, (Aim 3) Demonstrate heterogeneity of the tumor microenvironment and its contribution to tumor biology, and (Aim 4) Demonstrate heterogeneity and differential response to therapy. HER2 Crainbow mice will provide an autochthonous mouse model of the genetic heterogeneity found in HER2+ breast cancer, all while maintaining the endogenous contributions of the tumor microenvironment to invasion and metastasis. Completing this proposal is expected to validate the HER2 Crainbow mouse as a shareable resource strain for more predictive preclinical trials and a framework for illuminating the molecular and cellular ontogeny of invasive breast cancer.

摘要 乳腺癌的转基因小鼠模型已经被用作几十年的首要基础 机械发现的科学工具。然而，小鼠模型的成功实现， 治疗效果和转化研究的替代物一直是具有挑战性的。一个主要挑战 对于现状的方法是他们有限的能力来模拟乳腺癌中观察到的遗传异质性， 癌的转移性和耐药性HER 2+乳腺癌在很大程度上是不可治愈的， 异质性，其来源可能源于多种癌基因的竞争和进化， 驱动基因HER 2的同种型。该提案的目的是概括遗传学 HER 2癌基因在遗传上更接近人类的易处理模型中的异质性 条件-包括完整的免疫系统和基质网络。公布的初步数据 最近描述了一种用于荧光条形码化的癌症彩虹（Crainbow）建模系统， 在单个免疫完整小鼠中表达多个肿瘤驱动基因。荧光条形码是 通过多光谱成像和单细胞“组学”技术检索， 诱导肿瘤内异质性并可视化其演变。任何肿瘤驱动基因都可以 加入到彩虹鼠体内因此，本提案将检验中心假设， 在癌症彩虹小鼠中建立HER 2的致癌异质性模型 概括了在治疗耐药和转移性肿瘤中发现的表型异质性， HER 2+乳腺癌。中心假设将通过完成四个具体目标来检验 寻求：（目的1）建立HER 2 Crainbow小鼠肿瘤异质性模型，（目的2） 证明肿瘤上皮内的异质性，（目的3）证明肿瘤上皮的异质性， 肿瘤微环境及其对肿瘤生物学的贡献，以及（目的4）证明 异质性和对治疗的不同反应。HER 2彩虹小鼠将提供一个本地的 在HER 2+乳腺癌中发现的遗传异质性的小鼠模型，所有这些都同时维持了 肿瘤微环境对侵袭和转移的内源性贡献。完成本 一项提案预计将验证HER 2彩虹小鼠作为一种可共享的资源菌株， 预测性临床前试验和一个框架，用于阐明分子和细胞个体发育， 浸润性乳腺癌