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， Mouse intra-ductal（MIND）MIND涉及将源自患者DCIS的上皮细胞注射到 免疫受损小鼠的乳腺导管。DCIS MIND异种移植物显示了人类的全谱 DCIS包括侵袭性进展。进展为浸润的异种移植DCIS病变的组织学 结果显示，基底膜和肌上皮层被浸润细胞破坏， 肌上皮层和微浸润。因此，DCIS MIND模型是研究 DCIS侵袭性进展的早期分子机制， 患者DCIS。该提案旨在通过以下方式进一步改进MIND模型的翻译应用： 模拟小鼠中人DCIS的天然微环境，直接响应于该FOA。的 提出了以下具体目标（SA）：SA 1）用患者来源的人源化小鼠乳腺脂肪垫 永生化成纤维细胞和研究对DCIS进展为侵袭、病理学和生物标志物的影响 表情将评估DCIS异种移植物±人源化脂肪垫的病理学、生物标志物表达 并发展为入侵我们希望异种移植的DCIS与人源化乳腺脂肪垫， 在病理学和生物标志物表达方面与患者DCIS非常相似。我们还期望 人源化脂肪垫可增强一部分DCIS MIND异种移植物中DCIS的侵袭性进展。此外，本发明还 我们将DCIS上皮细胞固有的分子畸变（基因表达和/或基因组 畸变）与DCIS MIND异种移植物中DCIS侵袭行为的关系。SA 2）重构小鼠 用患者来源的免疫细胞治疗造血系统，并研究对DCIS进展的影响， 侵袭、病理学和生物标志物表达。实验过程包括重构 小鼠造血系统与患者来源的免疫细胞。我们将利用MISTRG小鼠，这种小鼠高度 允许人造血，包括支持单核细胞的发育和功能， 巨噬细胞和NK细胞。将评估DCIS异种移植物±患者源性免疫系统的人类免疫功能。 DCIS的免疫细胞浸润、DCIS病理和侵袭行为，如SA 1中所述。我们将把 DCIS特异性免疫细胞的募集以及DCIS上皮细胞固有的分子畸变 (gene表达和/或基因组畸变）与MIND异种移植物中DCIS侵袭行为的关系。