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.

项目概要 肿瘤转移仍然导致超过 65% 的癌症相关死亡率和几乎所有癌症相关死亡率 鉴于治疗转移性疾病的困难，预防措施。 阻止肿瘤细胞成功扩散到肺部等远处器官提供了一种 对于有乳腺癌风险的乳腺癌患者来说，具有吸引力且研究不足的治疗策略 原发性肿瘤通过重新编程来提高转移效率。 循环细胞到达之前远处肿瘤器官的微环境。 允许位点通常被称为“转移前生态位”（PMN）并经历 支持到达细胞的一系列细胞肿瘤和结构适应，包括 促进炎症和免疫抑制细胞的募集、新血管生成和 尽管血小板在止血中发挥典型作用，但它也是基质重塑不可或缺的一部分。 炎症性肺部疾病并调节 PMN I 采用的许多特征，因此， 我的初步数据支持这个说法， 证明血小板被隔离在转移前的肺部，并且降低血小板 计数减少了肺中性粒细胞的免疫细胞募集。为了扩展这些初步发现，这。 研究将确定血小板对肺 PMN 的贡献（目标 1），阐明 血小板影响肺转移前环境的机制（目标 2），并测试是否 治疗目标是转移前血小板数量或功能损害转移（目标 3）。 我将在获得K99奖励期间证明我的技术技能和科学专业知识 在我向独立研究员的转变中发挥了重要作用，我的长期目标是发展 针对有转移性乳腺风险的患者的新型预防和辅助治疗策略 为了实现这些长期目标，我制定了详细的职业发展计划，其中 将为我提供技术和领导技能来建立成功的研究 K99 阶段的研究将在实验室的出色（共同）指导下进行。 布里格姆和血液科的伊丽莎白·巴蒂内利 (Elisabeth Battinelli) 和桑德拉·麦卡利斯特 (Sandra McAllister) 博士 我的研究顾问委员会和合作者都是该领域的顶尖专家。 乳腺癌 PMN（Moses 博士）、血小板生成（Italiano 博士）以及靶向血小板 乳腺癌治疗（陈博士）。这个K99/R00奖项将为我提供无与伦比的支持。 我成功转型为研究血小板和癌症生物学的独立研究者。