Mechanisms governing metastatic dormancy and reactivation

控制转移休眠和重新激活的机制

基本信息

批准号：
9982048
负责人：
FILIPPO G GIANCOTTI
金额：
$ 96万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
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：
2016-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9982048
关键词：
Address Area Biology Blood Circulation Breast Cancer Biology Cells Clinic Clinical Data Detection Disease Distant Epigenetic Process Excision Foundations Generations Genes Genetic Screening Genetic Transcription Image Intervention Lesion Life Light Logic Lung Malignant Neoplasms Malignant neoplasm of pancreas Malignant neoplasm of prostate Mediator of activation protein Neoplasm Metastasis Operative Surgical Procedures Organ Pharmacology Phase Prevention Prostate Recurrence Relapse Research Seeds Signal Pathway Signal Transduction Site Therapeutic adult stem cell cancer cell cancer stem cell cancer type experimental study improved insight malignant breast neoplasm mathematical model metastasis prevention mouse model new therapeutic target novel novel marker programs public health relevance response stem cells temporal measurement therapeutic target

项目摘要

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.

描述（由适用提供）：小鼠模型中临床数据和实验的数学建模表明，从流行的癌症（例如乳腺癌和前列腺的癌症）中传播的癌细胞会在前移位部位进行长期休眠。甚至导致早期转移性继电器的癌症，例如胰腺癌，也可能在发现和切除前几年在循环和种子遥远的器官中产生循环前细胞。迫切需要深入了解使传播的癌细胞在休眠期间生存，然后逐渐扩大生命的课程的机制，以确定预防或治疗转移性治疗的新型治疗靶标疾病。通过使用一种新型的强大前瞻性基因筛查方法，我们已经确定了促进或抑制肺癌重新激活的基因。关于通过我们筛选确定的介体的机械研究表明，转移的启动细胞是癌细胞，或者在渗透目标器官时恢复到该状态，并且它们进入响应利基信号，细胞内信号通路和转录程序的休眠和重新激活，与调节正常成年干细胞的细胞相似。此外，这些研究产生了可行的治疗靶标。为了实现转移性休眠和重新激活的逻辑，并最终开发出一种新一代的药物，用于预防转移或治疗，现在有必要改善筛查的吞吐量，将研究扩展到其他殖民地现场和其他癌症类型，并通过空间和临时的先进的先进的现场图像来丰富我们的机械研究。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的更多基本问题以及驱动其重新激活并追求其他治疗靶标的表观遗传变化。我们的研究计划涵盖了三种癌症类型和多种目标器官，并旨在不仅阐明最神秘的转移阶段的生物学，而且还阐明了为诊所带来全新的疗法。