Gas6 regulation of premalignant mammary cells

项目摘要 导管原位癌（DCIS）是浸润前乳腺癌最常见的形式，占乳腺癌发病率的30%。 都被诊断为乳腺癌临床证据估计，约40%的DCIS患者未经治疗， 进展为浸润性乳腺癌。虽然，浸润前DCIS细胞获得细胞因子的机制是不明确的。 侵入邻近基质的能力在很大程度上是未知的。这些研究的长期目标是 了解当浸润前病变突破基底膜时发生的分子开关 侵入周围的基质这些研究旨在剖析巨噬细胞在 癌前病变，并确定机制，促进肿瘤侵入间质。使用小鼠 在早期进展模型中，我们已经表明巨噬细胞被募集到浸润前病变， 向致瘤表型极化，并分泌细胞因子Gas 6。我们假设巨噬细胞 在癌前病变的不同阶段发挥不同的功能，巨噬细胞来源的Gas 6促进了肿瘤的发生。 向侵袭性癌症转变。这一假设将通过以下目标进行检验： 巨噬细胞表型在浸润前病变，并确定其功能是否依赖于Gas 6。 目的2：确定基质来源的Gas 6对早期病变进展的贡献。我们 研究将利用几种小鼠模型，一个独特的三维培养系统，和单细胞RNA-seq来解剖 巨噬细胞源性Gas 6在癌前病变进展中的作用通过了解 入侵，这项研究可以确定生物标志物用于治疗，以预测患者的结果和指导 治疗这项研究的结果将大大提高我们对DCIS生物学的理解， 分期乳腺癌进展。通过这个奖学金的课程，我将学习不可或缺的技术， 提高我的写作和表达能力，并微调我的批判性思维能力。我已经形成了一个强大的 指导委员会来帮助填补我科学生涯中的空白。我将接受老鼠模型的训练， 乳腺癌生物学，人类和小鼠病理学，以及生物信息学，所有这些都将为我准备 我职业生涯的下一个阶段。我有机会接触到一个高度合作的，乳腺癌丰富的研究环境， 由基础科学家、临床医生、转化科学家和流行病学家组成。有优秀的核心 附近有多所大学和机构的设施。有很多机会 参加专业发展讲习班，以及参加优秀的研讨会和科学 撤退。我的赞助商，共同赞助商和我已经设计了具体的职业发展会议，将提高 我的培训，促进新的合作，并在发展成为一个领先的，独立的， 研究员

PROJECT SUMMARY Ductal carcinoma in situ (DCIS) is the most common form of pre-invasive breast cancer, accounting for 30% of all diagnosed breast cancers. Clinical evident estimates that ~40% of patients with DCIS left untreated will progress to invasive breast cancer. Although, the mechanisms by which pre-invasive DCIS cells acquire the ability to invade the adjacent stroma are largely unknown. The long-term research goals of these studies are to understand the molecular switch that occurs when pre-invasive lesions break through the basement membrane to invade the surrounding stroma. The proposed studies aim to dissect the role of macrophages in premalignancy and to identify the mechanisms that promotes tumor invasion into the stroma. Using mouse models of early progression, we have shown that macrophages are recruited to pre-invasive lesions and polarized toward a tumorigenic phenotype, and secret the cytokine Gas6. Our hypothesis is that macrophages exert distinct functions at different stages of premalignancy, and macrophage-derived Gas6 promotes the transition to invasive cancer. This hypothesis will be tested by the following aims: Aim 1: To characterize macrophage phenotypes in pre-invasive lesions and determine whether their function is dependent on Gas6. Aim 2: To determine the contribution of stromal-derived Gas6 on the progression of early stage lesions. Our studies will utilize several mouse models, a unique 3-D culture system, and single cell RNA-seq to dissect the role of macrophage-derived Gas6 in the progression of premalignancy. By understanding the mechanisms of invasion, this study could identify biomarkers to be used in therapeutics to predict patient outcome and direct treatment. The results of this study will significantly enhance our understanding of DCIS biology and early stage breast cancer progression. Through the course of this fellowship I will learn indispensable techniques, enhance my writing and presentation skills, and fine tune my critical thinking skills. I have formed a strong mentoring committee to help fill in the gaps in my scientific career. I will receive training in mouse models, breast cancer biology, human and mouse pathology, and bioinformatics, all of which will prepare me for the next stage of my career. I have access to a highly collaborative, breast cancer-rich research environment, comprised of basic scientists, clinicians, translational scientists, and epidemiologist. There are excellent core facilities from multiple universities and institutions within close proximity. There are many opportunities to participate in professional development workshops, as well as attend outstanding seminars and scientific retreats. My sponsor, co-sponsors and I have devised specific career development sessions that will enhance my training, facilitate new collaborations, and play an integral role in developing into a leading, independent researcher.