Cell Biological Mechanisms of Melanoma Cell Motility in vivo

黑色素瘤细胞体内运动的细胞生物学机制

• 批准号: 8891690
• 负责人: Minna Roh
• 金额: $ 11.44万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8891690
• 关键词: Ablation; Actins; Applications Grants; Award; Behavior; Biological; Biological Assay; Biological Models; Blood Vessels; Bypass; Cell Communication; Cell physiology; Cells; Cellular biology; Clinic; Clinical; Collaborations; Correlation Studies; Coupled; Coupling; Diagnosis; Disease; Distant Metastasis; Embryo; Environment; Event; Exhibits; Fellowship; Fishes; Focal Adhesions; Foundations; Fred Hutchinson Cancer Research Center; Genetic; Genetic Screening; Goals; Health; Human; Image; Immune; Immune system; In Vitro; Inflammatory; Inflammatory Response Pathway; Institutes; Institution; K-Series Research Career Programs; Larva; Life; Lymphatic vessel; Malignant Neoplasms; Maps; Medicine; Melanoma Cell; Mentors; Mentorship; Microscopy; Modeling; Mole the mammal; Mus; Neoplasm Metastasis; Nevus; Pathway interactions; Patients; Phase; Physicians; Postdoctoral Fellow; Premalignant; Process; Regulation; Reporter; Research; Research Personnel; Resolution; Role; Scientist; Signal Pathway; Signal Transduction; Skin; Stromal Cells; Stromal Neoplasm; Structure; Subcellular structure; Surface; Techniques; Testing; Therapeutic; Time; Transgenic Organisms; Tumor Cell Invasion; Universities; Washington; Xenograft procedure; Zebrafish; cancer cell; career; cell motility; cell type; cellular imaging; college; genetic approach; in vivo; in vivo Model; intravital imaging; macrophage; melanocyte; melanoma; migration; mouse model; neoplastic cell; new therapeutic target; novel marker; outcome forecast; research study; reverse genetics; time use; tumor; tumor microenvironment; tumor progression; tumorigenic

 DESCRIPTION (provided by applicant): It is unclear how a melanocyte transitions from a premalignant nevus to an invasive tumor cell; even less studied is the direct examination of this transition to motility in vivo. Zebrafish allows for high resolution imaging of tumor cell motility and zebrafish have melanocyte distribution that is similar to humans. Additionally, the progression of premalignant nevi to an early melanoma and later to an aggressive tumor is conserved between fish and humans. Thus, I will use human-in-fish xenotransplantation approaches as well as transgenic zebrafish strains to directly visualize melanoma cell motility. I will focus on how tumor associated macrophages facilitate specific steps of the metastatic cascade, specifically identifying the cell biological mechanisms regulating invadopodium formation by taking advantage of the amenability to high resolution imaging of zebrafish. I will then validate our key findings in mouse models with imaging window and fate mapping with photoconversion techniques. Importantly, I will discover how inflammatory response pathways regulate melanoma metastasis to better understand how immune cells and melanoma cells communicate in the microenvironment. The candidate for this career development award is a postdoctoral fellow, and the research proposed in this grant application will be conducted under the primary mentorship of Dr. Cecilia Moens, and under the co- mentorship of Dr. John Condeelis (Albert Einstein College of Medicine, NY) during the K99 phase of the award. The Moens lab at the Fred Hutchinson Cancer Research Center is an ideal environment for these studies due to the expertise of reverse genetics approaches, cell signaling, and live cell imaging strategies in zebrafish embryos. Dr. Condeelis is a world leader in the tumor microenvironment, and has expertise in both in vitro cytoskeletal regulation of tumor cell invasion, and intravital imaging of tumor cells in murine models. I will benefit immensely from the mentorship of Drs. Moens and Condeelis, and will bridge the expertise of both mentors toward understanding the dynamic cell-cell interactions regulating melanoma progression in fish and mouse models. The Fred Hutchinson Cancer Research Center is a world renowned cancer institute, and provides a wealth of cancer expertise: I have established collaborations with melanoma experts and physician- scientists within the Fred Hutchinson Cancer Research Center, at nearby University of Washington campuses, and with a melanoma clinical expert at MD Andersen. I am committed to a career as an independent investigator at an academic institution studying cancer cell biology, specifically studying the dynamic cytoskeletal mechanisms regulating tumor cell movements during metastasis. My current postdoctoral fellowship ends in August 2014. As I only been in Dr. Moens' lab for less than a year, the K99 award will give me enough time in her lab to develop this model further for me to set up the foundation for ongoing projects in my independent lab. My immediate goal is to define the tumor stromal signaling mechanisms regulating melanoma cell motility during metastasis. My long-term goal is to discover new markers and therapeutic targets for melanoma treatment.

 描述（申请人提供）：尚不清楚黑素细胞如何从癌前痣转变为侵袭性肿瘤细胞；甚至更少研究的是对体内这种向运动性转变的直接检查。斑马鱼可以对肿瘤细胞运动进行高分辨率成像，并且斑马鱼的黑素细胞分布与人类相似。此外，从癌前痣发展为早期黑色素瘤以及后来发展为侵袭性肿瘤的过程在鱼类和人类之间是保守的。因此，我将使用人鱼异种移植方法以及转基因斑马鱼品系来直接可视化黑色素瘤细胞的运动。我将重点关注肿瘤相关巨噬细胞如何促进转移级联的特定步骤，特别是利用斑马鱼高分辨率成像的优势来识别调节侵袭足形成的细胞生物学机制。然后，我将通过成像窗口和光转换技术的命运图谱来验证我们在小鼠模型中的主要发现。重要的是，我将发现炎症反应途径如何调节黑色素瘤转移，以更好地了解免疫细胞和黑色素瘤细胞在微环境中如何沟通。该职业发展奖的候选人是一名博士后研究员，本资助申请中提出的研究将在 Cecilia Moens 博士的主要指导下进行，并在该奖项的 K99 阶段由 John Condeelis 博士（纽约阿尔伯特爱因斯坦医学院）的共同指导下进行。弗雷德·哈钦森癌症研究中心的莫恩斯实验室拥有反向遗传学方法、细胞信号传导和斑马鱼胚胎活细胞成像策略方面的专业知识，是进行这些研究的理想环境。 Condeelis 博士是肿瘤微环境领域的世界领先者，在肿瘤细胞侵袭的体外细胞骨架调节和小鼠模型中肿瘤细胞的活体成像方面拥有专业知识。我将从博士的指导中受益匪浅。 Moens 和 Condeelis，并将结合两位导师的专业知识，了解在鱼和小鼠模型中调节黑色素瘤进展的动态细胞间相互作用。 Fred Hutchinson 癌症研究中心是世界著名的癌症研究所，提供丰富的癌症专业知识：我与 Fred Hutchinson 癌症研究中心、附近华盛顿大学校区的黑色素瘤专家和医师科学家以及 MD Andersen 的黑色素瘤临床专家建立了合作关系。我致力于在一家研究癌细胞生物学的学术机构担任独立研究员，专门研究转移过程中调节肿瘤细胞运动的动态细胞骨架机制。我目前的博士后研究将于 2014 年 8 月结束。由于我只在 Moens 博士的实验室工作了不到一年，K99 奖将使我有足够的时间在她的实验室进一步开发这个模型，为我的独立实验室正在进行的项目奠定基础。我的近期目标是确定转移过程中调节黑色素瘤细胞运动的肿瘤基质信号传导机制。我的长期目标是发现黑色素瘤治疗的新标记物和治疗靶点。