Deconstructing the Tumor Microenvironment and its Role in Metastasis

解构肿瘤微环境及其在转移中的作用

• 批准号: 9897462
• 负责人: Marjan Rafat
• 金额: $ 24.9万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9897462
• 关键词: 4T1; Advisory Committees; Affect; Area; Biological; Biological Factors; Biomechanics; Biomedical Engineering; Biomimetics; Blood specimen; Breast Cancer Model; Breast Cancer therapy; Breast Carcinoma; Cell Line; Cell model; Cells; Cicatrix; Clinic; Collaborations; Complex; Critical Pathways; Cues; Dependence; Development; Disease Progression; Dose; Educational workshop; Excision; Flow Cytometry; Foundations; Future; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Growth; Human; Imaging Techniques; Immune; Immune system; Immunohistochemistry; Individual; Infiltration; Inflammatory; Institution; Intervention; Ionizing radiation; Label; Laboratories; Laboratory Research; Lead; Link; Luciferases; MDA MB 231; Malignant Epithelial Cell; Mentors; Modeling; Molecular; Monitor; Morphology; Mus; Myeloid-derived suppressor cells; Neoplasm Circulating Cells; Neoplasm Metastasis; Normal tissue morphology; Operative Surgical Procedures; Pathway interactions; Patients; Play; Population; Process; Proliferating; Property; Radiation; Radiation therapy; Radiology Specialty; Recurrence; Regulation; Relapse; Research; Role; Series; Site; Stromal Neoplasm; Supervision; Surgical wound; Testing; Therapeutic Intervention; Tissues; Training Programs; Travel; Tumor Cell Migration; Tumor-infiltrating immune cells; Universities; Work; bioluminescence imaging; cancer cell; cancer recurrence; cancer therapy; career; cell motility; cytokine; design; experimental study; genetically modified cells; granulocyte; intervention effect; irradiation; macrophage; malignant breast neoplasm; mechanical properties; migration; mouse model; neoplastic cell; novel; novel therapeutics; orthotopic breast cancer; pre-clinical; public health relevance; radiation response; recruit; response; transcriptome sequencing; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment; tumor progression; wound; wound healing

 DESCRIPTION (provided by applicant): The objective of this proposal is to determine the microenvironmental factors responsible for tumor recurrence following therapy and to discover the underlying mechanisms. Previous studies have shown that tumor cells travel to sites of radiation as well as surgical scars from tumor excision, which leads to the hypothesis that the tumor microenvironment encourages circulating tumor cell migration following radiation and surgical therapies. This hypothesis will be tested using pre-clinical orthotopic breast cancer models to study how the microenvironment responds to radiotherapy and surgery and potentially influences cancer cell migration. My project is guided by three specific aims: (1) To determine how tumor-stromal interactions affect tumor cell migration, (2) to understand the role of the immune system in facilitating tumor cell migration, and (3) to investigate molecular pathways and biomechanical properties in the tumor microenvironment following therapy. A combination of biological, bioengineering, and imaging techniques will be used to evaluate the stated specific aims. Luciferase- and tdTomato-labeled human and mouse mammary carcinoma cells will be used to form orthotopic breast cancer models in mice. The course of tumor growth and migration after both radiation and surgery of normal tissues will be examined using bioluminescence imaging. Immune cell infiltration and distribution in treated areas will be assessed using immunohistochemistry and flow cytometry to identify recruited macrophages and myeloid derived suppressor cells. Granulocyte macrophage stimulating factor, an inflammatory cytokine known to play a role in tumor cell migration following radiation, will be monitored in both preclinical mouse and patient blood samples before and after therapy. Finally, changes in the tumor microenvironment after radiation and surgical therapy will be analyzed to determine factors that induce tumor cell migration. RNAseq will be used to evaluate the regulation of critical pathways involved in tumor cell migration and invasion. The mechanical properties of tissues following therapies will also be analyzed to discern the link between biological factors and physical cues in cancer progression and recurrence. Taken together, the results of these experiments will lead to the design of biomimetic tumor microenvironment models. Dr. Rafat's immediate goal is to determine whether microenvironmental response plays a role in modulating metastasis and relapse after therapy. This project will identify molecular mechanisms that influence tumor cell migration and invasion and examine the effect of interventional therapies themselves in facilitating disease progression. This work will lay the foundation for Dr. Rafat to establish an independent laboratory at an academic research institution. Her training program includes attendance at relevant seminars, workshops, and courses hosted by Stanford University as well as oversight from a mentor, co-mentor, and respected Career Advisory Committee to supervise both career and scientific development.

 描述（由申请人提供）：本提案的目的是确定治疗后肿瘤复发的微环境因素，并发现潜在机制。以前的研究表明，肿瘤细胞会迁移到放射部位以及肿瘤切除后的手术疤痕，这导致了肿瘤微环境鼓励放射和手术治疗后循环肿瘤细胞迁移的假设。这一假设将使用临床前原位乳腺癌模型进行测试，以研究微环境如何对放疗和手术做出反应，并可能影响癌细胞迁移。我的项目有三个具体目标：（1）确定肿瘤-基质相互作用如何影响肿瘤细胞迁移，（2）了解免疫系统在促进肿瘤细胞迁移中的作用，（3）研究治疗后肿瘤微环境中的分子途径和生物力学特性。生物学、生物工程学和成像技术的组合将用于评价所述特定目标。荧光素酶和tdTomato标记的人和小鼠乳腺癌细胞将用于在小鼠中形成原位乳腺癌模型。将使用生物发光成像检查正常组织的放射和手术后肿瘤生长和迁移的过程。将使用免疫组织化学和流式细胞术评估治疗区域的免疫细胞浸润和分布，以识别募集的巨噬细胞和髓源性抑制细胞。治疗前后，将在临床前小鼠和患者血样中监测粒细胞巨噬细胞刺激因子（一种已知在放射后肿瘤细胞迁移中发挥作用的炎性细胞因子）。最后，将分析放射和手术治疗后肿瘤微环境的变化，以确定诱导肿瘤细胞迁移的因素。RNAseq将用于评估参与肿瘤细胞迁移和侵袭的关键途径的调节。还将分析治疗后组织的机械特性，以识别癌症进展和复发中生物因素和物理线索之间的联系。综合起来，这些实验的结果将导致仿生肿瘤微环境模型的设计。Rafat博士的近期目标是确定微环境反应是否在调节治疗后的转移和复发中发挥作用。该项目将确定影响肿瘤细胞迁移和侵袭的分子机制，并检查介入治疗本身在促进疾病进展中的作用。这项工作将为Rafat博士在学术研究机构建立独立实验室奠定基础。她的培训计划包括参加由斯坦福大学主办的相关研讨会，研讨会和课程，以及导师，共同导师和受人尊敬的职业咨询委员会的监督，以监督职业和科学发展。

项目成果

Physicochemical Properties and Route of Systemic Delivery Control the In Vivo Dynamics and Breakdown of Radiolabeled Gold Nanostars.

• DOI: 10.1002/smll.202204293
• 发表时间: 2023-07
• 期刊: SMALL
• 影响因子: 13.3
• 作者: Wen, Xiaona;Ou, Luping;Cutshaw, Gabriel;Uthaman, Saji;Ou, Yu-Chuan;Zhu, Tian;Szakas, Sarah;Carney, Brandon;Houghton, Jacob;Gundlach-Graham, Alexander;Rafat, Marjan;Yang, Kai;Bardhan, Rizia
• 通讯作者: Bardhan, Rizia