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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的几十年来，转基因小鼠乳腺癌模型一直被用作首要的基础模型。然而，小鼠模型的成功实施。治疗效果和转化研究的替代物一直是一项重大挑战。对于现状方法来说，它们对乳房中观察到的遗传异质性进行建模的能力有限转移性和治疗耐药的 HER2+ 乳腺癌在很大程度上是无法治愈的。异质性，其根源可能源于多种致癌基因的竞争和进化驱动基因 HER2 的同种型该提案的目的是概括遗传基因。遗传易处理模型中 HER2 癌基因的异质性更紧密地重新组装人类状况 - 包括完整的免疫系统和基质网络。已发布的初步数据。最近描述了一种癌症彩虹（Crainbow）建模系统，用于荧光条形码和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，提供了一个简单的解决方案诱导肿瘤内异质性并可视化其进化可以是任何肿瘤驱动基因。因此，该提案将检验中心假设：对癌症彩虹小鼠中 HER2 的致癌异质性进行建模概括了治疗耐药性和转移性中发现的表型异质性 HER2+ 乳腺癌将通过完成四个具体目标来检验。寻求：（目标 1）验证 HER2 Crainbow 小鼠模型的肿瘤异质性，（目标 2）展示肿瘤上皮内的异质性，（目标 3）展示肿瘤上皮细胞的异质性肿瘤微环境及其对肿瘤生物学的贡献，以及（目标 4）展示 HER2 Crainbow 小鼠将提供本土治疗的异质性和差异反应。 HER2+乳腺癌中发现的遗传异质性小鼠模型，同时保持肿瘤微环境对侵袭和转移的内源性贡献。该提案预计将验证 HER2 Crainbow 小鼠作为可共享资源品系的更多用途预测性临床前试验和阐明分子和细胞个体发育的框架浸润性乳腺癌。