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

为了研究DCIS进展的分子机制，我们开发了一个模型 要当老鼠--导管内(心)。Mind涉及将来自患者DCIS的上皮细胞注射到 免疫功能低下小鼠的乳腺导管。DCIS异种心脏移植展示了人类的全光谱 DCIS包括侵袭性进展。进展为侵袭性的异种移植DCIS病变的组织学研究 显示基底膜和肌上皮层被侵袭性细胞破坏，回缩 肌上皮层和微侵袭。因此，DCIS心智模型是一种有价值的研究工具 DCIS侵袭性进展的早期分子机制因个体而异 病人DCIS。这一建议旨在通过以下方式进一步提高思维模式的翻译应用 在小鼠身上模拟人类DCIS的自然微环境，是对这种FOA的直接反应。这个 提出了以下特定目标(SA)：SA 1)将患者来源的小鼠乳房脂肪垫人性化 永生化成纤维细胞及其对DCIS侵袭、病理和生物标志物发展的影响 表情。将评估DCIS异种移植的人源化脂肪垫的病理、生物标志物的表达 并逐渐演变为入侵。我们希望植入人源化乳房脂肪垫的异种DCIS将有更多 在病理和生物标记物表达方面与患者DCIS非常相似。我们也期待着 人源化脂肪垫可增强部分DCIS异种脑移植的DCIS侵袭性进展。另外， 我们将DCIS上皮细胞固有的分子异常(基因表达和/或基因组 DCIS精神异种移植中的DCIS侵袭行为。SA 2)重建小鼠 患者来源免疫细胞的造血系统及其对DCIS进展的影响 侵袭、病理和生物标记物的表达。实验程序涉及到重建 具有患者来源免疫细胞的小鼠造血系统。我们将利用MISTRG小鼠，它们是高度 允许人类造血，包括支持单核细胞的发育和功能， 巨噬细胞和NK细胞。将为人类评估DCIS异种移植±患者来源的免疫系统 免疫细胞浸润与DCIS、DCIS病理和SA 1中描述的侵袭行为有关。我们将相关 特异性免疫细胞向DCIS的募集及DCIS上皮细胞固有的分子异常 (基因表达和/或基因组异常)与精神异种移植中的DCIS侵袭行为有关。

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.