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

• 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
• 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

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.

项目摘要/摘要 目前尚无旨在适当针对三重阴性/基础乳腺癌的可用疗法 亚型（TNBC）。由于初级治疗后发生复发和转移的风险，新的途径 必须采取干预。肿瘤基质，材料癌细胞生长，调节细胞 但是，增殖和生存，但是TNBC亚型特异性细胞外基质（ECM）和 TNBC耐药性的机制尚未产生。该建议将确定新颖的机制 基质在TNBC中诱导耐药性。使用3D体外筛选的组合，TNBC的鼠模型 和主要的患者样品，马丁博士将询问新型基质蛋白（胶原蛋白IV，XII和纤连蛋白） 参与TNBC耐药性。该建议的假设是：TNBC细胞外基质增强药物 通过诱导细胞休眠的抗性。马丁博士将使用体外3D肿瘤模型来筛选 基质组成对TNBC中细胞休眠和癌症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，为基质引起的免疫逃避提供了新的见解。这些体外屏幕将 通过构建和评估有条件敲除基质蛋白（胶原蛋白），可以在体内验证 IV，XII，纤连蛋白）在转基因鼠模型的乳腺脂肪垫中。最后，临床意义 研究将通过基质组成，免疫的询问和组织学评估来验证 浸润和细胞休眠的发生在TNBC原发性肿瘤中。马丁博士将使用蛋白质组学 评估原代TNBC和相邻匹配的组织的基质组成，并将这些发现与 观察到免疫浸润。还将进行其他组织学评估和确认。这会 通过以下特定目的进行调查：特定目标1。评估ECM组成对 TNBC耐药性。特定目的2。确定亚型特定ECM的翻译相关性 作品。