Tumor cytonemes, a new target for tumor suppression

肿瘤细胞因子，肿瘤抑制的新靶点

基本信息

批准号：
9247168
负责人：
THOMAS B. KORNBERG
金额：
$ 20.68万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9247168
关键词：
Adverse effects Appearance Attention Cancer Model Cell Communication Cells Cellular biology Chemicals Communication Communities Drosophila genus EGF gene Embryo Engineering Environment Epithelial Erinaceidae Fibroblast Growth Factor Filopodia Goals Growth Factor Hereditary Disease Homologous Gene Image Integral Membrane Protein K-ras mouse model Lead Length Limb structure Link Lung Adenocarcinoma Malignant Neoplasms Mediating Membrane Mesenchymal Modality Modeling Mus Neoplasm Metastasis Normal Cell Organ Organelles Paracrine Communication Patients Pharmaceutical Preparations Play Proteins Radiation Role SHH gene Signal Transduction Signaling Protein Stromal Cells Structure Synapses System Testing Tissues Toxin Transforming Growth Factor alpha Transforming Growth Factor beta Tumor Biology Tumor Cell Biology Tumor Stem Cells Tumor Suppression Work Zebrafish base cancer cell cancer therapy cell growth density mouse model mutant neoplastic cell novel public health relevance receptor response smoothened signaling pathway targeted treatment therapeutic target tumor tumor growth tumor microenvironment tumor progression tumorigenesis uptake

项目摘要

DESCRIPTION (provided by applicant): Recent progress in tumor biology has revealed that stromal cells - the non-transformed neighbors of tumor cells - play essential roles for tumor stem cells, tumor progression and metastasis. These roles involve communication between tumor and stromal cells, but the signals that are exchanged and the mechanism by which these signals move and elicit responses remain obscure. This is a proposal to build on our recent discovery that specialized organelles called cytonemes move and exchange signaling proteins between epithelial and mesenchymal cells in Drosophila - revealing that paracrine signaling in these normal contexts is mediated by cytonemes that make direct synaptic contacts between signaling cells. Importantly, we also identified mutant genetic conditions that compromised cytonemes and eliminated the contacts cytonemes normally make to mediate signaling, and showed that signaling was abrogated if cytonemes did not make direct synaptic contacts with target cells. All the paracrine signaling was cytoneme-dependent. We also tested the prediction that tumor cells communicate with stromal neighbors by a similar mechanism, and when we examined cells in a Drosophila tumor model, we detected cytonemes that extend from tumor cells to their normal neighbors. The presence of these organelles is consistent with the idea that they mediate signaling between tumor and stromal cells. The objective of the work proposed here is to investigate the role of cytonemes in tumorigenesis in Drosophila and mouse models. The goals are to identify where and in what form cytonemes are present, discover how cytonemes link tumor cells with their non-transformed neighbors, and determine whether cytoneme-mediated signaling is essential for the tumor growth. Based on previous studies, the likelihood that cytonemes are present and have essential roles in the vertebrate contexts is high. The proposed work may open a new avenue for controlling tumor growth, and by bringing this novel mechanism of cell-cell communication to the attention of the broader community of cancer biologists, it may alert them to the importance of cytoneme-mediated signaling and to the practicality of harnessing it for studies and therapy.

描述（由申请人提供）：肿瘤生物学的最新进展表明，基质细胞（肿瘤细胞的非转化邻居）在肿瘤干细胞、肿瘤进展和转移中发挥重要作用，这些作用涉及肿瘤和基质细胞之间的通讯。但交换的信号以及这些信号移动和引起反应的机制仍然不清楚，这是一项基于我们最近发现的提议，即称为细胞因子的特殊细胞器在上皮细胞和上皮细胞之间移动和交换信号蛋白。果蝇的间充质细胞 - 揭示了这些正常情况下的旁分泌信号传导是由细胞素介导的，细胞素在信号传导细胞之间进行直接的突触接触，重要的是，我们还发现了损害细胞素并消除了细胞素通常介导信号传导的接触的突变遗传条件，并表明。如果细胞因子不与靶细胞进行直接突触接触，信号传导就会被消除。我们还测试了肿瘤细胞与之通信的预测。基质邻居通过类似的机制，当我们检查果蝇肿瘤模型中的细胞时，我们检测到从肿瘤细胞延伸到其正常邻居的细胞因子。这些细胞器的存在与它们介导肿瘤和基质细胞之间的信号传导的想法是一致的。这里提出的工作的目的是研究细胞因子在果蝇和小鼠模型中肿瘤发生中的作用，目标是确定细胞因子存在的位置和形式，发现细胞因子如何将肿瘤细胞与它们联系起来。根据之前的研究，细胞因子存在并在脊椎动物中发挥重要作用的可能性很高，这项工作可能会开辟一条新途径。控制肿瘤生长，并通过使这种新的细胞间通讯机制引起更广泛的癌症生物学家的注意，它可能提醒他们细胞素介导的信号传导的重要性以及利用它进行研究和治疗的实用性。