Imaging endogenously produced tumor derived micro vesicles

描述(申请人提供)：虽然肿瘤细胞内源性基因突变是肿瘤进展的主要驱动力，但最近的研究表明，肿瘤细胞与宿主的外源性相互作用也深刻地调节了肿瘤的生长。具体地说，癌症的生长可能受多种免疫细胞类型的控制，这些细胞抑制或促进肿瘤的进展和转移，并可能部分地受到癌细胞的直接调节。这一应用程序致力于使用新技术来研究癌细胞如何与体内的远程细胞进行通信，以及这种通信是否以及如何影响癌症的生长。我们将专门研究肿瘤来源的微囊泡(TMV)作为肿瘤细胞和远离肿瘤间质的免疫细胞之间的信息传递者。TMV携带肿瘤衍生物质(蛋白质、mRNAs)，在体内进行短距离或长距离传播，同时保持其内容物不被降解和稀释，并可与远程组织中不同类型的宿主细胞相互作用(并通过延伸控制)；然而，TMV的生物学功能在很大程度上仍不清楚。在这一领域取得进展的一个关键障碍是我们有限的能力 了解体内内源性产生的移植物抗病毒药物的影响。事实上，到目前为止，关于TMV-免疫细胞相互作用的工作主体需要使用体外操纵的TMV，这可能不允许人们完全概括内源性产生的颗粒的特征。目前，免疫细胞与内源性TMV相互作用的确切位置和身份尚不清楚，这种相互作用对肿瘤进展的影响也是未知的。为了改变目前的实验研究方法，直接在体内研究tMV，这个为期两年的项目将结合：1)分子成像和2)新的遗传方法，以不同的分辨率和尺度(生物、细胞和分子)跟踪内源性产生的tMV及其靶标。这项研究的发现不仅应该验证在许多不同的实验环境中研究肿瘤细胞-宿主细胞相互作用的重要新工具，而且还将加深我们对tMvs的理解，并最终为抗癌治疗开辟新的途径。

DESCRIPTION (provided by applicant): Although tumor cell endogenous genetic mutations are major driving forces of tumor progression, recent work has established that cancer growth is also profoundly modulated by tumor cell exogenous interactions with its host. Specifically, cancer outgrowth may be controlled by various immune cell types, which either suppress or promote tumor progression and metastasis, and may be regulated in part by cancer cells directly. This application is dedicated to use new technology to investigate how cancer cells communicate with distant cells in the body, and whether and how this communication affects cancer growth. We will specifically study tumor-derived microvesicles (tMVs) as conveyors of information between tumor cells and immune cells that reside away from the tumor stroma. tMVs carry tumor-derived material (proteins, mRNAs), travel short or long distances in the body while keeping their contents undegraded and undiluted, and may interact with (and by extension control) different host cell types in remote tissues; however, the biological functions of tMVs remain largely unknown. A critical barrier to progress in the field has been our limited ability to understand the impact of tMVs that are produced endogenously in vivo. Indeed, the body of work on tMV-immune cell interactions so far has required the use of in vitro-manipulated tMVs, which may not allow one to fully recapitulate the features of endogenously produced particles. At present, the precise location and identity of immune cells interacting with endogenously produced tMVs is unknown, as is the impact of such interactions on tumor progression. To shift current experimental research approaches to study tMVs directly in vivo, this 2-year project will combine: 1) molecular imaging and 2) new genetic approaches to track endogenously produced tMVs and their targets at different resolutions and scales (organismal, cellular and molecular). Findings from this research should not only validate important new tools to study tumor cell-host cell interactions in many different experimental settings, but also deepen our understanding of tMVs and ultimately open up new avenues for anti-cancer therapy.