Identifying the Molecular and Cellular Basis of Invasive Phenotype in Human DCIS

鉴定人类 DCIS 侵袭表型的分子和细胞基础

• 批准号: 9311984
• 负责人: FARIBA BEHBOD
• 金额: $ 57.63万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-09 至 2020-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9311984
• 关键词: Adopted; Basement membrane; Behavior; Benign; Biological Markers; Biopsy; Blood Vessels; Blood capillaries; Breast; Cell Nucleus; Cells; Chromatin; Data; Development; Diagnosis; Disease; ERBB2 gene; Engraftment; Epithelial Cells; Exhibits; Fatty acid glycerol esters; Fibroblasts; Gene Expression; Growth; Hematopoiesis; Hematopoietic System; Histologic; Histology; Human; Immune; Immune system; Immunoassay; Immunocompromised Host; In Situ; Infiltration; Injectable; Injection of therapeutic agent; Invasive Lesion; Lesion; Mammary Duct; Mammary gland; Modeling; Molecular; Molecular Abnormality; Mus; Myoepithelial; Natural Killer Cells; Noninfiltrating Intraductal Carcinoma; Observational Study; Operative Surgical Procedures; Pathology; Patient observation; Patients; Phenotype; Procedures; Radiation; Recruitment Activity; Recurrence; Reporting; Risk; Time; Translations; Xenograft procedure; base; capillary; cost; genetic manipulation; genomic aberrations; high risk; hormone therapy; improved; in vivo; macrophage; monocyte; mortality; mouse model; neoplastic cell; patient subsets; permissiveness; reconstitution; tool; unnecessary treatment

In order to study the molecular mechanisms underlying DCIS progression, we developed a model that we refer to as mouse-intraductal (MIND). MIND involves injection of epithelial cells derived from patient DCIS into the mammary ducts of immunocompromised mice. DCIS MIND xenografts exhibited the full spectrum of human DCIS including invasive progression. Histology of xenografted DCIS lesions that progressed to invasion showed disruption of basement membrane and myoepithelial layer by the invasive cells, retraction of myoepithelial layer and microinvasion. Therefore, the DCIS MIND model is a valuable tool for studying the early molecular mechanisms underlying DCIS invasive progression in a manner that is individualized to each patient DCIS. This proposal that is aimed at further improving the translation application of MIND models by mimicking the natural microenvironment of human DCIS in mice, is directly responsive to this FOA. The following specific aims (SA) are proposed: SA 1) Humanize mouse mammary fat pads with patient derived immortalized fibroblasts and study effects on DCIS progression to invasion, pathology and biomarker expression. The DCIS xenografts ± humanized fat pads will be assessed for pathology, biomarker expression and progression to invasion. We expect the xenografted DCIS with humanized mammary fat pads to more closely resemble patient DCIS with respect to pathology and biomarker expression. We also expect the humanized fat pads to enhance DCIS invasive progression in a fraction of DCIS MIND xenografts. Additionally, we will correlate DCIS epithelial cell inherent molecular aberrations (gene expression and/or genomic aberrations) to DCIS invasive behavior in the DCIS MIND xenografts. SA 2) Reconstitute the mouse hematopoietic system with patient derived immune cells and study effects on DCIS progression to invasion, pathology and biomarker expression. The experimental procedure involves reconstitution of mouse hematopoietic system with patient derived immune cells. We will utilize MISTRG mice, which are highly permissive for human hematopoiesis including support of the development and function of monocytes, macrophages and NK cells. DCIS xenografts ± patient derived immune system will be assessed for human immune cell infiltration to DCIS, DCIS pathology and invasive behavior as described in SA 1. We will correlate the recruitment of specific immune cells to DCIS as well as DCIS epithelial cell inherent molecular aberrations (gene expression and/or genomic aberrations) to DCIS invasive behavior in the MIND xenografts.

为了研究DCIS进展的分子机制，我们开发了一个模型，我们参考 作为鼠标内部（思维）。思维涉及注射从患者DCIS衍生成的上皮细胞 免疫功能低下的小鼠的乳腺管道。 DCIS的思维Xenographictic揭露了人类的全部范围 DCI包括侵入性进展。异种移植DCIS病变的组织学，发展为入侵 显示出侵入性细胞对基底膜和肌上皮层的破坏，缩回 肌上皮层和微侵入。因此，DCIS心理模型是研究 DCIS侵入性进展的早期分子机制以一种个性化的方式 患者DCIS。该建议旨在进一步改善思维模型的翻译应用 模仿小鼠人类DCI的天然微环境直接响应该FOA。这 提出了以下特定目的（SA）：SA 1）患者得出的小鼠乳腺脂肪垫人性化 永生的成纤维细胞和研究对DCIS侵袭，病理学和生物标志物的研究影响 表达。 DCIS异种移植物±人源脂肪垫将评估病理学，生物标志物表达 和入侵的进展。我们期望带有人源化乳腺脂肪垫的异种移植DCI会增加 在病理学和生物标志物表达方面，与患者DCI紧密相似。我们也期望 人源化脂肪垫，以增强DCIS Xenographictics的DCIS侵入性进展。此外， 我们将将DCIS上皮细胞继承分子畸变（基因表达和/或基因组 DCIS侵入性行为的畸变）。 SA 2）重建鼠标 造血系统具有患者衍生的免疫细胞，并研究对DCIS发展的影响 入侵，病理和生物标志物表达。实验程序涉及重组 小鼠造血系统，具有患者衍生的免疫球。我们将利用Misstrg小鼠，这是高度的 人类造血的允许性，包括支持单核细胞的发展和功能， 巨噬细胞和NK细胞。 DCIS Xenographictics±患者衍生的免疫抑制系统将被评估 SA 1中所述的免疫细胞浸润对DCI，DCIS病理和侵入性行为。我们将相关 特异性免疫细胞募集到DCIS以及DCIS上皮细胞遗传分子畸变 （基因表达和/或基因组畸变）在思维Xenographictic中进行DCIS侵入性行为。