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.

项目总结/摘要 目前没有设计用于适当靶向三阴性/基底乳腺癌的可用疗法 亚型（TNBC）。由于主要治疗后复发和转移的风险， 必须进行干预。肿瘤基质是癌细胞生长的物质， 然而，TNBC亚型特异性细胞外基质（ECM）与TNBC亚型特异性细胞外基质（ECM）之间的联系， TNBC耐药机制尚未确定。该提案将确定新的机制， 基质诱导的TNBC耐药性。使用3D体外筛选的组合，TNBC的鼠模型， 和主要患者样本，马丁博士将询问新的基质蛋白（胶原蛋白IV，XII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抵抗。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的诱导的影响。 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，提供了新的见解基质诱导的免疫逃避。这些体外筛选将 通过构建和评估基质蛋白（胶原蛋白）的条件性敲除进行体内验证 IV，XII，纤连蛋白）。最后，对该方法的临床意义进行了探讨。 研究将通过询问和基质成分、免疫组织化学和组织学评价进行验证。 在一组TNBC原发性肿瘤中观察到细胞浸润和细胞休眠的发生。马丁博士将利用蛋白质组学 评估原发性TNBC和邻近匹配组织的基质组成，并将这些发现与 观察到免疫浸润。还将进行额外的组织学评价和确认。这将 通过以下具体目标进行调查：具体目标1。评价ECM组合物对细胞生长的影响。 TNBC耐药性。具体目标2。确定亚型特异性ECM的翻译相关性 混合物.