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: 10202445
• 负责人: Margaret Ellen Shevik
• 金额: $ 3.76万
• 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/10202445
• 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; GTP-Binding Protein alpha Subunits, Gs; Genomic DNA; Gland; Growth; Immune; Inflammation; Inflammatory; Integrins; Knockout Mice; Label; Lactation; Laminin; Light; Link; Liquid Chromatography; Lung Inflammation; Malignant - descriptor; Malignant Neoplasms; Mammary gland; Mediating; Modeling; Mothers; Mus; Mutagenesis; Neoplasm Metastasis; Normal tissue morphology; Pathologic; Pathway interactions; Peptide Hydrolases; Pharmacology; Phase; Physiological; Pre-Clinical Model; Preventive therapy; Process; Prognosis; Proliferating; Protein Isoforms; Proteins; Proteolysis; Publishing; Research; Risk; Role; Signal Transduction; Site; Testing; Time; Tissues; Tobacco use; Weaning; Woman; Work; cancer cell; cell growth; extracellular; insight; intravital imaging; intravital microscopy; knock-down; malignant breast neoplasm; neutrophil; 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.

项目总结 中性粒细胞胞外陷阱(Net)是基因组DNA的网状结构，与释放的相关酶有关 中性粒细胞在炎症过程中。我们之前发表的数据证实了网络相关的蛋白酶 能够触发静止的癌前细胞变得增殖。为了做到这一点，篮网重塑了 细胞外基质蛋白层粘连蛋白产生一种整合素激活表位，从而触发增殖。然而， 在生理性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 核扩散是未知的。乳腺退化--乳腺恢复到正常状态的过程。 妊娠状态-以导管细胞凋亡和显著的细胞外基质重塑为特征。 这一过程与伤口愈合过程惊人地相似，包括中性粒细胞最初流入组织。 乳腺复旧创造了一个促进肿瘤的利基环境，并被建议与 发生产后乳腺癌，占以下妇女乳腺癌病例的一半 40岁。为了支持进一步的研究和从治疗上针对NETS的行动的能力，它是 确定网络重塑的层粘连蛋白表位及其可能激活的整合素受体所必需的。 此外，NETS对组织重塑计划和肿瘤促进环境的贡献 乳腺退行性变的原因尚不清楚。在这个阶段研究网络可能会提供更深层次的 从整体上了解乳腺退缩，并找出预防的机会 产后乳腺癌的治疗--这是一种特别具有破坏性的疾病，因为它的预后很差， 增加转移性疾病的风险，并对年幼儿童的母亲产生影响。我假设那张网 重塑产生层粘连蛋白表位，激活整合素信号，刺激血管内皮细胞增殖 乳腺退行性变中的癌前细胞。该项目将建立层粘连蛋白表位和 它激活整合素受体，这将提供关于静止细胞如何被触发的关键信息 增殖，并将产生工具来进一步研究这一途径。此外，这个项目将有助于 确定Net在退化过程中的具体作用，以及它们是否可能是治疗的良好靶点。这是 这也是一个令人兴奋的机会，可以利用活体成像来确定中性粒细胞如何对组织做出贡献 乳腺退缩过程中的重塑以及我们如何从药物上靶向网络重塑 在临床前模型中防止癌前细胞生长。这项提案将调查篮网如何促进 在乳腺退化的背景下，通过组织重塑转变为恶性肿瘤。最终，这项工作 在这项建议中产生的不仅将为更深入地理解NETS的机制奠定基础 它不仅用于治疗恶性肿瘤，而且还用于开发产后乳腺癌的预防性治疗方法。