Neutrophil-mediated tissue remodeling in postpartum breast cancer

中性粒细胞介导的产后乳腺癌组织重塑

• 批准号: 10673964
• 负责人: Margaret Ellen Shevik
• 金额: $ 5.27万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10673964
• 关键词: Age Years; Antibodies; Apoptosis; Breast Cancer Cell; Cell Line; Cell Proliferation; Cells; Characteristics; Child; DNA; Data; Development; Disease; Ductal Epithelial Cell; Environment; Epitopes; Extracellular Matrix; Extracellular Matrix Proteins; Extracellular Space; Future; Genomic DNA; Gland; Growth; Immune; Inflammation; Inflammatory; Integrins; Knockout Mice; Label; Lactation; Laminin; Light; Link; Liquid Chromatography; Malignant - descriptor; Malignant Neoplasms; Mammary gland; Mediating; Modeling; Mothers; Mus; Mutagenesis; Neoplasm Metastasis; Normal tissue morphology; Pathologic; Pathway interactions; Peptide Hydrolases; Phase; Physiological; Pre-Clinical Model; Preventive therapy; Process; Prognosis; Proliferating; Protein Isoforms; Proteins; Proteolysis; Publishing; Pulmonary Inflammation; Research; Risk; Role; Signal Transduction; Site; Testing; Time; Tissues; Tobacco use; Tumor Promotion; Weaning; Woman; Work; cancer cell; cell growth; extracellular; insight; intravital imaging; intravital microscopy; knock-down; malignant breast neoplasm; neoplastic; neutrophil; pharmacologic; postpartum breast cancer; preneoplastic cell; prepregnancy; prevent; programs; receptor; response; tandem mass spectrometry; targeted treatment; therapeutic target; three dimensional cell culture; tool; tumor; wound healing

PROJECT SUMMARY Neutrophil extracellular traps (NETs) are meshes of genomic DNA with associated proteases that are released by neutrophils during inflammation. Our previously published data established that NET-associated proteases are capable of triggering quiescent, preneoplastic cells to become proliferative. To do this, NETs remodel the extracellular matrix protein laminin to produce an integrin-activating epitope that triggers proliferation. However, whether NETs activated during physiologic tissue remodeling similarly trigger this switch from quiescence to proliferation is unknown. Mammary gland involution—the process by which the gland returns to its pre- pregnancy state—is characterized by apoptosis of ductal cells and significant extracellular matrix remodeling. This process is strikingly similar to that of wound healing, including an initial influx of neutrophils to the tissue. Mammary gland involution creates a tumor-promotional niche and is suggested to be associated with the development of postpartum breast cancer, which accounts for half of all breast cancer cases in women under 40 years of age. To support further research and the ability to therapeutically target the action of NETs, it is necessary to determine the NET-remodeled laminin epitope and which integrin receptors it may activate. Additionally, the contribution of NETs to the tissue remodeling program and the tumor-promotional environment of the involuting mammary gland is still unknown. Studying NETs in this phase may provide a deeper understanding of mammary gland involution as a whole, as well as identify opportunities for preventative therapies against postpartum breast cancer—a particularly devastating disease due to its poor prognosis, increased risk of metastatic disease, and effect on the mothers of young children. I hypothesize that NET remodeling generates a laminin epitope that activates integrin signaling to stimulate the proliferation of preneoplastic cells during mammary gland involution. This project will establish the laminin epitope and the integrin receptors it activates, which will provide crucial information on how quiescent cells may be triggered to proliferate, and will generate tools to further investigate this pathway. Additionally, this project will help determine the specific role of NETs during involution and if they may be a good target for therapies. This is also an exciting opportunity to utilize intravital imaging to determine how neutrophils may contribute to tissue remodeling during mammary gland involution and how we may pharmacologically target NET remodeling to prevent preneoplastic cell growth in a preclinical model. This proposal will investigate how NETs may promote to malignancy through tissue remodeling in the context of mammary gland involution. Ultimately, the work generated in this proposal will set the stage not only for a deeper understanding of the mechanisms of NETs within malignancies, but also for the development of preventative therapies for postpartum breast cancer.

项目摘要 神经细胞外陷阱（NET）是基因组DNA与相关蛋白酶的网状物， 由中性粒细胞引起我们以前发表的数据表明，NET相关蛋白酶 能够触发静止的癌前细胞增殖。为了做到这一点，NET重新设计了 细胞外基质蛋白层粘连蛋白，以产生触发增殖的整合素活化表位。然而，在这方面， 在生理组织重塑过程中激活的NET是否类似地触发了这种从静止到静止的转换， 扩散是未知的。乳腺退化-腺体返回到其前的过程， 妊娠状态-特征在于导管细胞的凋亡和显著的细胞外基质重塑。 这一过程与伤口愈合惊人地相似，包括中性粒细胞最初流入组织。 乳腺退化创造了一个肿瘤促进的生态位，并建议与乳腺癌的发生有关。 产后乳腺癌的发展，占所有乳腺癌病例的一半， 40岁为了支持进一步的研究和治疗靶向NET作用的能力， 这是确定NET重塑的层粘连蛋白表位和它可能激活的整合素受体所必需的。 此外，NET对组织重塑计划和肿瘤促进环境的贡献 还不清楚退化的乳腺。在这个阶段研究NET可以提供更深入的 了解乳腺退化作为一个整体，以及确定预防的机会， 针对产后乳腺癌的治疗-由于其预后差而特别具有破坏性的疾病， 增加转移性疾病的风险，并影响幼儿的母亲。我假设， 重塑产生层粘连蛋白表位，其激活整合素信号传导以刺激细胞增殖。 乳腺退化过程中的癌前细胞。该项目将建立层粘连蛋白表位和 它激活的整合素受体，这将提供关于静止细胞如何被触发的关键信息， 扩散，并将产生进一步研究这一途径的工具。此外，该项目将有助于 确定在退化过程中NET的具体作用，以及它们是否可能成为治疗的良好靶点。这是 这也是一个令人兴奋的机会，利用活体成像，以确定如何中性粒细胞可能有助于组织 乳腺退化期间的重塑以及我们如何将NET重塑靶向于 在临床前模型中防止癌前细胞生长。这项建议将探讨母语英语教师如何促进 在乳腺退化的背景下，通过组织重塑转化为恶性肿瘤。最终，工作 本建议中产生的信息不仅可以为更深入地了解NET的机制奠定基础， 在恶性肿瘤中，而且还用于开发产后乳腺癌的预防性治疗。