Mechanisms governing metastatic dormancy and reactivation

控制转移休眠和重新激活的机制

• 批准号: 10474409
• 负责人: FILIPPO G GIANCOTTI
• 金额: $ 95.55万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 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/10474409
• 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

 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（由申请人提供）：临床数据和小鼠模型实验的数学模型表明，从常见癌症（例如乳腺癌和前列腺癌）传播的癌细胞在转移前部位经历了较长的休眠期。导致早期转移性复发的疾病，例如胰腺癌，可能会在循环中产生转移前细胞，并在检测和切除之前几年在远处器官中播种。为了确定预防或治疗转移性肿瘤的新治疗靶点，迫切需要在休眠期间存活下来，然后长成危及生命的病变。 通过使用一种新颖的强大的正向遗传筛选方法，我们已经确定了促进或抑制肺部乳腺癌重新激活的基因，通过我们的筛选确定的介质的机制研究表明，转移起始细胞是癌症干细胞或逆转细胞。渗透到目标器官后进入这种状态 休眠并响应与调节正常成体干细胞相似的生态位信号、细胞内信号通路和转录程序而重新激活。此外，这些研究已经产生了可行的治疗靶标，以充分了解转移性休眠和转移的逻辑。重新激活并最终开发新一代用于预防或治疗转移的药物，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位点和其他癌症类型，并丰富我们的机制研究在这些研究提供的基础上，利用先进实时成像的空间和时间分辨率，将有可能解决有关转移干细胞的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，不仅旨在阐明最神秘的转移阶段的生物学，而且还为临床带来全新的治疗方法。

项目成果

A heterotrimeric SMARCB1-SMARCC2 subcomplex is required for the assembly and tumor suppression function of the BAF chromatin-remodeling complex.

BAF 染色质重塑复合物的组装和肿瘤抑制功能需要异三聚体 SMARCB1–SMARCC2 亚复合物

• DOI: 10.1038/s41421-020-00196-4
• 发表时间: 2020
• 期刊: Cell discovery
• 影响因子: 33.5
• 作者: Chen G;Zhou H;Liu B;Wang Y;Zhao J;Giancotti FG;Long J
• 通讯作者: Long J

Prostate epithelial genes define therapy-relevant prostate cancer molecular subtype.

• DOI: 10.1038/s41391-021-00364-x
• 发表时间: 2021-12
• 期刊: Prostate cancer and prostatic diseases
• 影响因子: 4.8
• 作者: Han H;Lee HH;Choi K;Moon YJ;Heo JE;Ham WS;Jang WS;Rha KH;Cho NH;Giancotti FG;Choi YD
• 通讯作者: Choi YD