Evaluation of Subtype Specific Collagen Remodeling in Breast Cancer Progression

项目摘要/摘要 目前还没有针对三阴性/基础乳腺癌的有效治疗方法。 亚型(TNBC)。由于初级治疗后复发和转移的风险，新的治疗途径 必须进行干预。肿瘤基质是癌细胞生长的物质，它调节细胞 增殖和存活之间的联系，然而，TNBC亚型特异性细胞外基质(ECM)和 TNBC耐药机制尚不清楚。这项建议将确定新的机制， 基质诱导TNBC耐药。使用3D体外筛选、TNBC小鼠模型、 和初级患者样本，马丁博士将询问新的基质蛋白(IV型、XII型胶原和纤维连接蛋白) 与TNBC耐药有关。这一建议的假设是：TNBC细胞外基质增强药物 通过诱导细胞休眠产生的抗性。马丁博士将使用体外3D肿瘤模型来筛选 基质成分对TNBC细胞休眠和肿瘤干细胞表型诱导的影响。 此外，马丁博士将确定在不同基质复合材料上生长的癌细胞如何改变T细胞 激活和增殖，为研究基质诱导的免疫逃避提供了新的视角。这些体外筛查将 通过构建和评价条件性敲除基质蛋白(胶原蛋白)在体内得到验证 IV、XII、FN)在转基因小鼠乳房脂肪垫中的表达。最后，本研究的临床意义。 研究将通过讯问和组织学评估基质成分，免疫 一组TNBC原发肿瘤的浸润和细胞休眠的发生。马丁博士将利用蛋白质组学 评估原发TNBC和邻近匹配组织的基质成分，并将这些发现与 观察到免疫渗入。还将进行额外的组织学评估和确认。这将是 通过以下具体目标进行调查：具体目标1.评估ECM组成对 TNBC耐药。特定目标2.确定亚型特定ECM的翻译相关性 组成。

Project Summary/Abstract Currently there are no available therapies designed to appropriately target the triple negative/basal breast cancer subtype (TNBC). Due to the risk of recurrence and metastasis following primary therapy, novel avenues of intervention must be pursued. The tumor matrix, the material cancer cells are grown on, modulates cellular proliferation and survival, however a link between a TNBC subtype specific extracellular matrix (ECM) and mechanisms of TNBC drug resistance has not yet been made. This proposal will identify novel mechanism of matrix induced drug resistance in TNBC. Using a combination of 3D in vitro screens, murine models of TNBC, and primary patient samples, Dr. Martin will interrogate novel matrix proteins (collagen IV, XII, and fibronectin) involved in TNBC drug resistance. The hypothesis of this proposals is: TNBC extracellular matrix enhances drug resistance through the induction of cellular dormancy. Dr. Martin will use in vitro 3D tumor models to screen the effects of matrix composition on induction of cellular dormancy and a cancer stem cell phenotype in TNBC. Furthermore Dr. Martin will determine how cancer cells grown on different matrix composites alter T-cell activation and proliferation, providing new insight on matrix induced immune evasion. These in vitro screens will be validated in vivo through the construction and evaluation of conditional knock out of matrix proteins (collagen IV, XII, fibronectin) in the mammary fat pad of transgenic murine models. Finally the clinical significant of this study will be verified through the interrogation and histological evaluation of matrix composition, immune infiltration, and occurrence of cell dormancy in a panel TNBC primary tumors. Dr. Martin will use proteomics to evaluate the matrix composition of primary TNBC and adjacent matched tissue and correlate these finding with observed immune infiltration. Additional histological evaluation and confirmation will also be performed. This will be investigated through the following specific aims: Specific Aim 1. Evaluate the effect of ECM composition on TNBC drug resistance. Specific Aim 2. Determine the translational relevance of subtype specific ECM composition.