The Role of Platelets in Establishing the Lung Pre-Metastatic Niche in Breast Cancer

血小板在乳腺癌肺转移前生态位建立中的作用

• 批准号: 10721733
• 负责人: Harvey George Roweth
• 金额: $ 17.82万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10721733
• 关键词: Adjuvant; Adjuvant Therapy; Adopted; Advisory Committees; Affect; Antiplatelet Drugs; Attention; Award; Blood Platelets; Blood Vessels; Bone Marrow; Breast Cancer Patient; Breast Cancer therapy; Breast cancer metastasis; CXCL5 gene; Cancer Biology; Cell Survival; Cell physiology; Cells; Cessation of life; Circulation; Clinical; Communication; Data; Development Plans; Disease; Distant; Distant Metastasis; Drug Targeting; Environment; Goals; Hematology; Hemostatic function; Hospitals; Immune; Impairment; Inflammation; Inflammatory; Knowledge; Laboratory Research; Leadership; Leukocytes; Lung; Malignant Neoplasms; Megakaryocytes; Mentorship; Metastatic Neoplasm to the Lung; Metastatic breast cancer; Mus; Myelogenous; Myeloid Cells; Neoplasm Circulating Cells; Neoplasm Metastasis; Organ; Outcome; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phase; Platelet Activation; Platelet Count measurement; Pre-Clinical Model; Preventive; Primary Neoplasm; Process; Production; Protein-Lysine 6-Oxidase; Pulmonary Inflammation; Research; Research Personnel; Research Proposals; Risk; Role; S100A8 gene; Series; Signal Transduction; Site; Small Interfering RNA; T-Lymphocyte; Technical Expertise; Testing; Therapeutic; Therapeutic Research; Toxic effect; Tumor Cell Invasion; Tumor-Derived; United States; Woman; angiogenesis; cancer cell; cancer therapy; career development; curative treatments; cytokine; design; improved outcome; inflammatory lung disease; malignant breast neoplasm; monocyte; mortality; neoplastic cell; novel; permissiveness; platelet function; preservation; programs; recruit; skills; therapeutic evaluation; therapeutic target; transcriptomics; triple-negative invasive breast carcinoma; tumor; tumor-immune system interactions

PROJECT SUMMARY Tumor metastasis remains responsible for >65% of cancer-associated mortality and nearly all breast cancer deaths. Given the difficulties in treating metastatic disease, preventive approaches that block the successful dissemination of tumor cells to distant organs like the lung offer an attractive and under-researched therapeutic strategy for breast cancer patients at risk of metastatic disease. Primary tumors increase metastatic efficiency by reprogramming the microenvironment of distant organs before the arrival of circulating tumor cells. These tumor- permissive sites are commonly referred to as the “pre-metastatic niche” (PMN) and undergo a series of cellular and structural adaptations that support arriving tumor cells, including the recruitment of inflammation-promoting and immunosuppressive cells, neoangiogenesis, and stromal remodeling. Despite their archetypal roles in hemostasis, blood platelets are integral to inflammatory lung diseases and regulate many of the hallmarks adopted by the PMN. I, therefore, hypothesize that platelets promote the lung PMN. My preliminary data support this statement, demonstrating that platelets are sequestered in pre-metastatic lungs and that lowering platelet counts reduces immune cell recruitment to the lung PMN. To expand on these initial findings, this research will determine the contributions of platelets to the lung PMN (Aim 1), elucidate mechanisms by which platelets impact the lung pre-metastatic environment (Aim 2), and test if therapeutically targeting pre-metastatic platelet number or function impairs metastasis (Aim 3). The technical skills and scientific expertise I will obtain throughout the K99 award period will prove instrumental in my transition into an independent researcher, with the long-term goal to develop novel preventative and adjuvant therapeutic strategies for patients at risk of metastatic breast cancer. To reach these long-term goals, I have outlined a detailed career development plan, which will provide me with the technical and leadership skills to establish a successful research laboratory. The K99 phase of research will be conducted under the excellent (co)mentorship of Drs. Elisabeth Battinelli and Sandra McAllister at the Hematology Division of Brigham and Women’s Hospital. My Research Advisory Committee and collaborators are leading experts in the breast cancer PMN (Dr. Moses), platelet production (Dr. Italiano), and targeting platelets for breast cancer therapy (Dr. Chen). This K99/R00 award will provide me unparalleled support for my successful transition to an independent investigator studying platelet and cancer biology.

项目摘要 肿瘤转移仍然负责> 65％的癌症相关死亡率，几乎全部 乳腺癌死亡。考虑到治疗转移性疾病的困难，预防方法 这样可以阻止像肺这样成功地传播肿瘤细胞到远处的器官 乳腺癌患者有吸引力和研究不足的治疗策略 转移性疾病。原发性肿瘤通过重新编程提高转移性​​效率 循环肿瘤细胞到达之前，远处器官的微环境。这些肿瘤 - 允许的地点通常称为“前转移利基市场”（PMN），并经历了 一系列支持到达肿瘤细胞的细胞和结构适应，包括 募集炎症和免疫抑制细胞，新血管生成和 基质重塑。尽管血小板在止血中具有原型作用，但仍是不可或缺的 炎症性肺部疾病并调节PMN采用的许多标志。因此，我 假设血小板促进了肺部PMN。我的初步数据支持此语句 证明血小板是隔离肺中的隔离，并降低血小板 计数可将免疫细胞募集降低到肺PMN。为了扩展这些初步发现， 研究将确定血小板对肺PMN的贡献（AIM 1），阐明 血小板影响肺前转移环境（AIM 2）的机制，并测试是否 治疗靶向物转移的血小板数或功能会损害转移（AIM 3）。 我将在整个K99奖励期内获得的技术技能和科学专业知识将证明 在我转变为独立研究人员的过程中，具有长期目标的发展 针对有转移性乳房风险的患者的新型预防性和可调治疗策略 癌症。为了实现这些长期目标，我概述了一个详细的职业发展计划，该计划 将为我提供技术和领导能力，以建立成功的研究 实验室。 K99研究阶段将在优秀（CO）的指导下进行 博士。 Brigham和 妇女医院。我的研究咨询委员会和合作者是领先的专家 乳腺癌PMN（摩西博士），血小板生产（Italiano博士）和针对血小板的 乳腺癌疗法（陈博士）。这个K99/R00奖将为我提供无与伦比的支持 我成功地过渡到研究血小板和癌症生物学的独立研究者。