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

摘要 几十年来，乳腺癌的转基因小鼠模型一直被用作主要的基础 机械发现的科学工具。然而，鼠标模型的成功实现为 替代品的治疗效果和转化研究一直是具有挑战性的。一大挑战 对于现状方法来说，他们对乳房中观察到的遗传异质性进行建模的能力有限 癌症。转移性和耐药的HER2乳腺癌在很大程度上是无法治愈的 异质性，其来源可能源于多个致癌基因的竞争和进化 驱动基因HER2的异构体。这项建议的目标是概括基因 HER2癌基因的异质性在一个更接近人类的遗传易驯化模型中 状况--包括完整的免疫系统和基质网络。已公布的初步数据 最近描述了一种用于荧光条形码和癌症彩虹的建模系统 在一个免疫完整的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，提供了一种简单的解决方案 诱导肿瘤内的异质性并使其演变可视化。任何肿瘤驱动基因都可以是 被整合到彩虹小鼠身上。因此，这一提议将检验核心假设，即 HER2基因在彩虹癌小鼠体内致癌异质性的模拟 概括了在耐药和转移瘤中发现的表型异质性。 她患了2例乳腺癌。核心假设将通过完成四个具体目标来检验 寻求：(目标1)验证肿瘤异质性的HER2彩虹小鼠模型，(目标2) 显示肿瘤上皮内的异质性，(目标3)显示肿瘤上皮的异质性 肿瘤微环境及其对肿瘤生物学的贡献，以及(目标4)展示 治疗的异质性和差异性反应。HER2彩虹小鼠将提供一个原生的 在HER2乳腺癌中发现遗传异质性的小鼠模型，所有这些都保持了 肿瘤微环境对侵袭和转移的内源性贡献。完成这项工作 该提案预计将验证HER2 Cainrow鼠标是否为可共享的资源压力，以获得更多 预测性临床前试验和阐明肿瘤分子和细胞个体发生的框架 浸润性乳腺癌。

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.