Evaluation of Subtype Specific Collagen Remodeling in Breast Cancer Progression

乳腺癌进展中亚型特异性胶原重塑的评估

基本信息

批准号：
10579213
负责人：
Elizabeth Martin
金额：
$ 22.19万
依托单位：
LOUISIANA STATE UNIV A&M COL BATON ROUGE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2023-03-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10579213
关键词：
3-Dimensional 4T1 Address Basement membrane Cell Aging Cell Line Cell Proliferation Cell Separation Cells Cellular Infiltration Cellular Stress Chemoresistance Clinical Clustered Regularly Interspaced Short Palindromic Repeats Collagen Collagen Type IV Collection Data Drug Sensitization Drug resistance Elastic Fiber Evaluation Exhibits Extracellular Matrix Extracellular Matrix Proteins Fatty acid glycerol esters Fibronectins Growth Factor Histologic Immune Immune Evasion In Vitro Intervention Link Mediating Modeling Molecular Mus Neoplasm Metastasis Oncology Organ Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Preparations Phenotype Primary Neoplasm Prognosis Prognostic Marker Proliferating Proteins Proteomics Recurrence Regulation Research Risk Sample Size Sampling Signal Transduction Slide T cell infiltration T-Cell Activation TP53 gene Testing The Cancer Genome Atlas Time Tissues Transgenic Organisms Tumor Volume United States National Institutes of Health anticancer research bioprinting breast cancer progression cancer cell cancer cell subtype cancer drug resistance cancer stem cell cancer subtypes conditional knockout experimental study immune cell infiltrate in vivo innovation insight malignant breast neoplasm mammary molecular subtypes mouse model novel novel marker novel therapeutics pre-clinical recruit resistance mechanism therapy design therapy resistant treatment response triple-negative invasive breast carcinoma tumor tumorigenesis

项目摘要

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.

项目概要/摘要目前还没有专门针对三阴性/基底乳腺癌的可用疗法亚型（TNBC）。由于主要治疗后存在复发和转移的风险，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，调节细胞增殖和存活，然而 TNBC 亚型特异性细胞外基质 (ECM) 和 TNBC耐药机制尚未阐明。该提案将确定新的机制 TNBC 中基质诱导的耐药性。结合使用 3D 体外屏幕、TNBC 小鼠模型、马丁博士将研究新型基质蛋白（IV 型胶原蛋白、XII 型胶原蛋白和纤连蛋白）参与 TNBC 耐药性。该提案的假设是：TNBC细胞外基质增强药物通过诱导细胞休眠来产生抵抗力。 Martin博士将利用体外3D肿瘤模型来筛选基质成分对 TNBC 中细胞休眠诱导和癌症干细胞表型的影响。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，为基质诱导的免疫逃避提供了新的见解。这些体外筛选将通过构建和评估条件敲除基质蛋白（胶原蛋白）进行体内验证 IV、XII，纤连蛋白）在转基因小鼠模型的乳腺脂肪垫中。最后这个的临床意义研究将通过基质成分、免疫学的询问和组织学评估来验证一组 TNBC 原发性肿瘤中的浸润和细胞休眠的发生。马丁博士将利用蛋白质组学来评估原发性 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浸润。还将进行额外的组织学评估和确认。这将通过以下具体目标进行研究：具体目标 1. 评估 ECM 组合物对 TNBC 耐药性。具体目标 2. 确定亚型特异性 ECM 的翻译相关性作品。