Do Tumor-Immune Interactions Prime Systemic Tolerance of Triple-Negative Breast Cancer Brain Metastases?

肿瘤免疫相互作用是否会导致三阴性乳腺癌脑转移的全身耐受性？

• 批准号: 10735596
• 负责人: Maxine Chidinma Umeh Garcia
• 金额: $ 16.26万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10735596
• 关键词: Advisory Committees; African American; African ancestry; Architecture; Award; Biological; Brain; Brain Neoplasms; Breast; Breast Cancer Patient; Cause of Death; Cell Communication; Cells; Central Nervous System Diseases; Cerebrospinal Fluid; Cessation of life; Clinical; Complex; Data; Development; Development Plans; Diagnosis; Diffuse; Disease; Disease Progression; Ensure; Environment; Ethnic Origin; Event; Foundations; Genes; Genetic Transcription; Goals; Human; Image Analysis; Immune; Immune Targeting; Immune Tolerance; Immune mediated destruction; Immune system; Immunologic Receptors; In Situ; Incidence; Leptomeninges; Ligands; Machine Learning; Malignant Neoplasms; Mammary Neoplasms; Maps; Measures; Mentors; Metastatic malignant neoplasm to brain; Methods; Modeling; Molecular; Molecular Target; Multiplexed Ion Beam Imaging; Neoplasm Metastasis; Patient-Focused Outcomes; Patients; Phase; Population; Primary Neoplasm; Prognosis; Proteins; Public Health; RNA; Race; Research; Research Personnel; Research Training; Resolution; Resources; Sampling; Science; Structure; Surface; Systems Biology; Testing; Therapeutic; Tissue Sample; Training; Universities; Visualization; Woman; Work; analysis pipeline; biocomputing; brain cell; brain tissue; cancer cell; cancer health disparity; career; career development; data integration; differential expression; high risk; human disease; human tissue; imaging modality; immune cell infiltrate; immunogenic; improved; innovation; malignant breast neoplasm; molecular imaging; mortality; multiplexed imaging; neoplastic cell; new therapeutic target; novel therapeutic intervention; receptor; research and development; single-cell RNA sequencing; skills; statistics; survival outcome; therapy resistant; tool; transcriptome sequencing; transcriptomics; triple-negative invasive breast carcinoma; tumor; tumor microenvironment; tumor progression; tumor-immune system interactions

PROJECT SUMMARY / ABSTRACT It is widely estimated that 90% of cancer-related deaths are caused by metastasis. This statistic underscores our inability to manage cancer once it disseminates through the body, and our need to better understand molecular mechanisms that drive metastasis. Triple-negative breast cancer (TNBC) occurs in 15% of breast cancer cases. Taken as a group, TNBCs pose an unmet clinical challenge in many ways: (1) TNBCs represents the most aggressive and most metastatic subtype of breast cancer, (2) up to 46% of TNBC patients will develop brain metastases, (3) TNBC patients are at four-times higher risk of developing diffuse metastases on the brain surface (leptomeningeal disease), which is rapidly and universally fatal, and (4) women of African ancestry have an up to 80% higher likelihood of developing TNBC – making TNBC a cancer disparity. Previous studies demonstrate that primary TNBC is highly immunogenic, and immune infiltration is associated with improved prognosis. However, little is known about the immune environment in TNBC brain metastases and how tumor-immune interactions effect metastatic potential. Recognizing these pressing issues, I have chosen to focus my career as an independent researcher on using systems biology approaches to uncover molecular mechanisms that underlie metastasis, and ethnicity-specific cancer disparities. A comprehensive mentoring, research, and career development plan will be executed over the course of the K99 and R00 training periods, which will provide me with the necessary tools to make a successful transition to independence. To visualize tumor-immune interactions, I will construct an in-situ protein map of TNBC brain metastases using MIBI – a cutting-edge multiplexed imaging method (AIM 1). I will quantitate the composition and spatial architecture of the microenvironment; and determine the extent to which these features correlate with patient outcomes. In AIM 2, I will identify tumor-immune receptor-ligand pairs using single-cell RNA-sequencing on TNBC brain metastases samples. Lastly, in AIM 3, I will use MIBI to visualize tumor-immune interactions in primary TNBCs to determine whether interactions in the primary tumor microenvironment prime systemic tolerance of disseminated tumor cells, enabling brain metastases. I will validate relevant targets by measuring their expression in patient cerebrospinal fluid (CSF), which contains brain-tumor-associated cell-free RNA. My proposed research will positively impact public health as it will reveal key tumor-immune interactions responsible for priming the immune system for metastasis; and will generate the first “TNBC brain metastasis interactome”. My results will lead to the discovery of new molecular targets with the primary goal of reducing metastasis-driven cancer mortality. The K99 career development plan and focused research training will be critical to expand my skillset in biocomputation – a necessary component of my proposed research; as well as fill any gaps in my background, preparing me for a timely and successful transition to the R00 phase. Overall, the dual-phase award will significantly enhance my research and ensure my continued contribution to public health and increasing diversity in science, as an established cancer researcher.

项目摘要/摘要 据广泛估计，90%的癌症相关死亡是由转移引起的。这一统计数据强调了我们的 一旦癌症在体内扩散，我们就无法控制它，以及我们需要更好地了解分子 驱动转移的机制。三阴性乳腺癌(TNBC)发生在15%的乳腺癌病例中。 作为一个群体，TNBCs在许多方面构成了一个未被满足的临床挑战：(1)TNBCs代表着最具侵略性的 和大多数转移亚型的乳腺癌，(2)高达46%的TNBC患者会发生脑转移，(3)TNBC 患者发生脑表面弥漫性转移(软脑膜疾病)的风险是对照组的四倍。 这是迅速和普遍致命的，(4)非洲血统的妇女患上这种疾病的可能性高达80% 发展TNBC-使TNBC成为癌症差距。以前的研究表明，主要的TNBC是高度 免疫原性和免疫浸润与改善预后有关。然而，人们对此知之甚少 TNBC脑转移的免疫环境及肿瘤-免疫相互作用对转移的影响 潜力。认识到这些紧迫的问题，我选择了将我作为独立研究员的职业生涯集中在使用 系统生物学方法揭示转移和种族特定癌症的分子机制 差距。本课程将实施一项全面的指导、研究和职业发展计划。 K99和R00培训阶段，这将为我提供必要的工具，以使 向独立过渡。 为了可视化肿瘤与免疫的相互作用，我将使用以下方法构建TNBC脑转移的原位蛋白质图 MIBI--一种前沿的多路成像方法(AIM 1)。我将量化的组成和空间架构 微环境；并确定这些特征与患者预后相关的程度。在《目标2》中，我会 应用单细胞RNA测序技术在TNBC脑转移瘤标本中鉴定肿瘤-免疫受体-配体对。 最后，在AIM 3中，我将使用MIBI可视化原发TNBCs中的肿瘤-免疫相互作用，以确定 原发肿瘤微环境中的相互作用启动播散性肿瘤细胞的全身耐受，使大脑 转移瘤。我将通过测量它们在患者脑脊液(CSF)中的表达来验证相关靶点 含有脑瘤相关的无细胞RNA。我提议的研究将对公众健康产生积极影响 揭示负责启动免疫系统以防止转移的关键肿瘤-免疫相互作用；并将产生 首个“TNBC脑转移相互作用组”。我的结果将导致发现新的分子靶标与初级 目标是降低因转移而导致的癌症死亡率。K99职业发展计划和重点研究 培训将是扩大我在生物计算方面的技能的关键--这是我提议的研究的必要组成部分； 以及填补我背景中的任何空白，为我及时而成功地过渡到R00阶段做好准备。 总体而言，两个阶段的奖项将显著加强我的研究，并确保我继续为公众做出贡献 作为一名公认的癌症研究人员，他在科学方面的健康和日益多样化。