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 肿瘤转移仍然是造成超过65%的癌症相关死亡率和几乎所有死亡率的原因 乳腺癌死亡人数考虑到治疗转移性疾病的困难， 阻断肿瘤细胞向肺部等远处器官的成功扩散， 有吸引力和研究不足的治疗策略，为乳腺癌患者的风险， 转移性疾病原发性肿瘤通过重编程肿瘤细胞来增加转移效率。 在循环肿瘤细胞到达之前，远端器官的微环境。这些肿瘤- 允许位点通常被称为“转移前小生境”（PMN），并经历一个 一系列细胞和结构适应，支持到达肿瘤细胞，包括 炎症促进细胞和免疫抑制细胞的募集，新血管生成，以及 基质重塑尽管血小板在止血中起着典型的作用，但它们是血液中不可或缺的一部分。 炎症性肺部疾病和调节PMN采用的许多标志。因此， 假设血小板促进肺PMN。我的初步数据支持这一说法， 表明血小板被隔离在转移前的肺中， 计数减少免疫细胞向肺PMN的募集。为了扩大这些初步发现，这 研究将确定血小板对肺PMN的贡献（目的1），阐明 血小板影响肺转移前环境的机制（目标2），并测试 治疗靶向转移前血小板数量或功能损害转移（目的3）。 我将在整个K99奖励期间获得的技术技能和科学专业知识将证明 帮助我过渡到一个独立的研究人员，长期目标是发展 转移性乳腺癌风险患者的新型预防和辅助治疗策略 癌为了实现这些长期目标，我制定了详细的职业发展计划， 将为我提供技术和领导技能，以建立一个成功的研究 实验室K99阶段的研究将在以下优秀的（共同）指导下进行： Drs.布里格姆血液科的伊丽莎白·巴蒂内利和桑德拉·麦卡利斯特， 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（Moses博士），血小板生成（Dr. Italiano）和靶向血小板 乳腺癌治疗（陈医生）。这个K99/R 00奖将为我提供无与伦比的支持， 我成功转型为一名研究血小板和癌症生物学的独立研究者。