Mechanisms governing metastatic dormancy and reactivation

 描述（由申请人提供）：临床数据的数学建模和小鼠模型中的实验表明，从流行性癌症（如乳腺癌和前列腺癌）传播的癌细胞在转移前部位经历延长的休眠期。即使是导致早期转移复发的癌症，如胰腺癌，也可能在检测和切除前几年在循环中产生转移前细胞并在远处器官中播种。迫切需要深入了解使播散的癌细胞能够在休眠期间存活然后生长成危及生命的病变的机制，以便确定用于预防或治疗转移性癌的新的治疗靶点。 疾病通过使用一种新的强大的向前遗传筛选方法，我们已经确定了促进或抑制乳腺癌在肺中再活化的基因。对通过我们的筛选鉴定的介质的机制研究表明，转移起始细胞是癌症干细胞或在浸润靶器官后恢复到这种状态，并且它们进入靶器官。 休眠并响应于小生境信号、细胞内信号传导途径和转录程序而经历再活化，所述小生境信号、细胞内信号传导途径和转录程序类似于调节正常成体干细胞的那些。此外，这些研究已经产生了可操作的治疗靶点。为了充分理解转移休眠和再激活的逻辑，并最终开发新一代用于转移预防或治疗的药物，现在有必要提高我们的筛选通量，将我们的研究扩展到其他定植部位和其他癌症类型，并利用先进的实时成像的空间和时间分辨率来丰富我们的机制研究。在这些研究提供的基础上，将有可能解决有关转移性干细胞起源和驱动其重新激活的表观遗传变化的更基本问题，并寻求其他治疗靶点。我们的研究项目涵盖三种癌症类型和多个靶器官，旨在不仅揭示转移最神秘阶段的生物学，而且为临床带来全新的治疗方法。

 DESCRIPTION (provided by applicant): Mathematical modeling of clinical data and experiments in mouse models suggest that cancer cells disseminating from prevalent cancers, such as those of the breast and prostate, undergo an extended period of dormancy at pre-metastatic sites. Even cancers, which causes early metastatic relapse, such as pancreatic cancer, may spawn pre-metastatic cells in the circulation and seed distant organs several years before their detection and resection. Insights into the mechanisms that enable disseminated cancer cells to survive during dormancy and then outgrow into life-threatening lesions are sorely needed in order to identify novel therapeutic targets for the prevention or treatment of metastatic disease. By using a novel powerful forward genetic screening approach, we have identified genes that promote or suppress reactivation of breast cancer in the lung. Mechanistic studies on the mediators identified through our screens suggest that the metastasis-initiating cells are cancer stem cells or revert to this state upon infiltrating a target organ and that they enter into dormancy and undergo reactivation in response to niche signals, intracellular signaling pathways and transcriptional programs which are similar to those that regulate normal adult stem cells. In addition, these studies have yielded actionable therapeutic targets. In order to fuly understand the logic of metastatic dormancy and reactivation and ultimately develop a new generation of agents to be used for metastasis prevention or therapy, it is now necessary to improve the throughput of our screens, to extend our studies to other colonization sites and other cancer types, and to enrich our mechanistic studies with the spatial and temporal resolution of advanced live imaging. On the foundation provided by these studies, it will then be possible to address more fundamental questions about the origin of metastatic stem cells and the epigenetic changes that drive their reactivation and to pursue additional therapeutic targets. Our research program spans three cancer types and multiple target organs and aims to not only shed light on the biology of the most mysterious phase of metastasis but also to bring to the clinic an entire new class of therapeutics.