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Investigating Wnt and Lgr5 signaling as regulators of lung cancer heterogeneity

研究 Wnt 和 Lgr5 信号作为肺癌异质性调节因子

基本信息

批准号：
8925034
负责人：
Tuomas Tammela
金额：
$ 12.29万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-09 至 2017-09-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8925034
关键词：
Ablation Accounting Adenocarcinoma Cell Alleles Area Award Biological Cancer Etiology Cancer cell line Cell Communication Cell Differentiation process Cell Line Cell Lineage Cells Cessation of life Collaborations Communities Complement Data Development Disease Dreams Educational workshop Environment Failure Family Family member Fellowship Fostering Foundations Funding Gene Expression Gene Expression Profiling Genetic Goals Grant Health Heterogeneity Human Human Cell Line Institutes Internal Ribosome Entry Site Intervention Knock-in Mouse Label Laboratories Lead Learning Lentivirus Vector Literature Lung Adenocarcinoma Lung Neoplasms Lymphangiogenesis Malignant Neoplasms Malignant neoplasm of lung Maps Mentors Methodology Mission Modeling Molecular Mus National Cancer Institute Non-Small-Cell Lung Carcinoma Oncogenic Outcome Pathway interactions Phenotype Positioning Attribute Postdoctoral Fellow Principal Investigator RNA Interference Reagent Reporter Research Role Series Shapes Signal Pathway Signal Transduction Solid Stem cells Students Subfamily lentivirinae System Tamoxifen Testing Therapeutic Training Training Programs Transplantation Treatment outcome Tumor Angiogenesis Tumor Subtype Work anticancer research base cancer cell cancer stem cell cancer therapy chemotherapy design experience improved in vivo inhibitor/antagonist medical schools mouse model novel novel marker paracrine programs promoter receptor recombinase research study response skills small molecule stem stemness targeted treatment therapeutic target tool treatment response tumor tumor initiation tumor progression undergraduate student

项目摘要

DESCRIPTION (provided by applicant): Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death globally. Tumors driven by expression of oncogenic Kras account for approximately 25% of NSCLC subtypes and, for these tumors in particular, effective chemotherapies are lacking. One possible explanation for the failure of standard chemotherapies in these tumors is the cellular heterogeneity that exisists within tumors. The goal of this proposal is to understand the cellular heterogeneity in Kras-driven lung adenocarcinoma. Specifically, I will explore the role of the Wnt and R-spondin/Lgr5 family signaling pathways as a paracrine regulators of cellular de-differentiation and "stemness" in the tumors. To do so, I will employ a series of novel tools in a sophisticated mouse model of Kras- driven lung adenocarcinoma as well as in human lung adenocarcinoma cell lines. I propose to test the role of the Wnt and R-spondin/Lgr pathways in lung tumor initiation and progression, as well as potential targets of therapy. To do this, I will use small molecule inhibitors of Wnt synthesis or dual-promoter lentiviruses to silence key components of the pathway, including Lgr5 family receptors, using RNAi. Furthermore, novel Wnt reporter lentiviruses or knock-in alleles expressing Lgr5 or Lgr6 driven and tamoxifen-activatable CreER recombinase will be used to perform lineage-tracing experiments that allow me to track the fate of or ablate the putative lung adenocarcinoma stem cells in a tumor model that undergoes natural tumor progression and is not based on cell line transplantation, a caveat in most of the current literature. Use of Wnt-responsive and Lgr5/6 reporters will also enable me to isolate the putative lung adenocarcinoma stem cells for gene expression profiling, which may lead to the discovery of novel stem cell markers and druggable pathways. Elucidating the molecular mechanisms that regulate cell (differentiation) states in cancer will provide novel markers for mapping the cellula landscape of tumors; some will prove to be useful targets for pharmacological intervention, which will eventually improve treatment outcomes in this largely intractable disease. Thus, I feel that this proposal is fully aligned with the mission of the National Cancer Institute. In this application I also propose an extensive training program that is designed to facilitate my transition to an independent Principal Investigator position. The research environment in the Jacks Laboratory, MIT, and the surrounding area offers unparalleled opportunities for scientific discussion, collaboration and training. I currently supervise an undergraduate student and a technical assistant that work directly with me on experiments pertaining to my research. This is an incredible experience that will endow me with many of the necessary skills to manage an independent laboratory. The scientific community at MIT, the Broad Institute, and Harvard Medical School offers countless courses, seminars and workshops that will continue to foster my scientific development. I have been fortunate in having been able to assemble a dream team of Mentors (Dr. Jacks and Dr. Weinberg) and Consultants (Dr. Clevers and Dr. Scadden), who will provide me with the necessary guidance and support throughout the entire duration of the K99/R00 Award. Importantly, my Primary Mentor Dr. Jacks will allow me to take all of my current and proposed research with me to serve as the foundation of my future research program. The research proposed within this application has been shaped by my experiences in studying cell-cell interactions controlling (tumor) angiogenesis and lymphangiogenesis, as well as by the past 2 years in the Jacks Laboratory learning novel methodology and concepts. I intend to start an independent research program that will capitalize on these powerful in vivo systems. I have already demonstrated my independence by creating a project in a field not previously studied in our lab as well as by obtaining independent funding in the form of Fellowships and small project grants. This, in combination with the large number of reagents that I have developed, provides me with the momentum needed to complete the proposed program. For the long-term, I am confident that these experiments will provide a solid foundation on which my research program can be built upon. I look forward to mentoring students and postdocs that share my passion for cancer research.

描述（由申请方提供）：非小细胞肺癌（NSCLC）是全球癌症相关死亡的主要原因。由致癌Kras表达驱动的肿瘤约占NSCLC亚型的25%，特别是对于这些肿瘤，缺乏有效的化疗。标准化疗在这些肿瘤中失败的一个可能的解释是肿瘤内存在的细胞异质性。本提案的目的是了解Kras驱动的肺腺癌中的细胞异质性。具体来说，我将探讨Wnt和R-spondin/Lgr 5家族信号通路作为肿瘤中细胞去分化和“干性”的旁分泌调节因子的作用。为此，我将在Kras驱动的肺腺癌的复杂小鼠模型以及人肺腺癌细胞系中采用一系列新工具。我建议测试Wnt和R-spondin/Lgr通路在肺肿瘤发生和发展中的作用，以及潜在的治疗靶点。为此，我将使用Wnt合成的小分子抑制剂或双启动子慢病毒来沉默该途径的关键组分，包括使用RNAi的Lgr 5家族受体。此外，新型Wnt报告基因慢病毒或表达Lgr 5或Lgr 6驱动和他莫昔芬激活的CreER重组酶的敲入等位基因将用于进行谱系追踪实验，使我能够在经历自然肿瘤进展的肿瘤模型中追踪或消融推定的肺腺癌干细胞的命运，而不是基于细胞系移植，这是目前大多数文献中的警告。使用Wnt应答和Lgr 5/6报告基因也将使我能够分离出推定的肺腺癌干细胞进行基因表达谱分析，这可能会导致发现新的干细胞标志物和药物途径。阐明调节癌症细胞（分化）状态的分子机制将为绘制肿瘤细胞景观提供新的标志物;一些将被证明是药物干预的有用靶点，最终将改善这种主要难治性疾病的治疗结果。因此，我认为这项建议完全符合国家癌症研究所的使命。在本申请中，我还提出了一个广泛的培训计划，旨在促进我过渡到一个独立的主要研究者的位置。在杰克实验室，麻省理工学院和周边地区的研究环境提供了科学讨论，合作和培训无与伦比的机会。我目前监督一名本科生和一名技术助理，他们直接与我一起进行与我的研究有关的实验。这是一个令人难以置信的经验，将赋予我许多必要的技能来管理一个独立的实验室。麻省理工学院、布罗德研究所和哈佛医学院的科学界提供了无数的课程、研讨会和讲习班，这些将继续促进我的科学发展。我很幸运能够组建一个由导师（Jacks博士和温伯格博士）和顾问（Clevers博士和Scadden博士）组成的梦之队，他们将在K99/R 00奖的整个期间为我提供必要的指导和支持。重要的是，我的主要导师杰克博士将允许我把我所有的当前和拟议的研究与我一起作为我未来的研究计划的基础。本申请中提出的研究是由我在研究控制（肿瘤）血管生成和淋巴管生成的细胞-细胞相互作用方面的经验以及过去2年在Jacks实验室学习新方法和概念形成的。我打算启动一个独立的研究项目，利用这些强大的体内系统。我已经通过在我们实验室以前没有研究过的领域创建一个项目以及通过获得奖学金和小型项目赠款形式的独立资金来证明我的独立性。这与我开发的大量试剂相结合，为我提供了完成拟议计划所需的动力。从长远来看，我相信这些实验将为我的研究计划奠定坚实的基础。我期待着指导学生和博士后分享我对癌症研究的热情。