Mechanisms governing metastatic dormancy and reactivation

控制转移休眠和重新激活的机制

• 批准号: 8956183
• 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
• 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/8956183
• 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; 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; Phase; Prevention; Prostate; Recurrence; Relapse; Research; Seeds; Signal Pathway; Signal Transduction; Site; Stem cells; Therapeutic; Work; adult stem cell; cancer cell; cancer stem cell; cancer type; improved; insight; malignant breast neoplasm; mathematical model; metastasis prevention; mouse model; new therapeutic target; novel; novel marker; programs; public health relevance; research study; response; temporal measurement; therapeutic target

 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(申请人提供)：临床数据的数学建模和在小鼠模型中的实验表明，从常见癌症(如乳腺癌和前列腺癌)扩散的癌细胞在转移前部位经历了较长的休眠期。即使是导致早期转移复发的癌症，如胰腺癌，也可能在发现和切除前几年在循环中滋生转移前细胞，并在远处器官种植。为了确定预防或治疗转移的新的治疗靶点，迫切需要深入了解使播散性癌细胞在休眠期间存活并随后长成危及生命的病变的机制。 疾病。通过使用一种新的强大的正向基因筛查方法，我们已经确定了促进或抑制肺癌复发的基因。对通过我们的筛查确定的介质的机制研究表明，启动转移的细胞是癌症干细胞，或者在渗透到靶器官后恢复到这种状态，并且它们进入 细胞处于休眠状态，并在小生境信号、细胞内信号通路和转录程序的响应下重新激活，这些信号和转录程序类似于调节正常成年干细胞的程序。此外，这些研究还产生了可操作的治疗靶点。为了全面了解转移休眠和再激活的逻辑，并最终开发用于转移预防或治疗的新一代药物，现在有必要提高我们的筛查的吞吐量，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，将有可能解决更基本的问题，即转移干细胞的来源以及驱动它们重新激活的表观遗传学变化，并寻求其他治疗靶点。我们的研究项目跨越三种癌症类型和多个靶器官，旨在不仅阐明最神秘的转移阶段的生物学，而且为临床带来一种全新的治疗方法。