Functional Analysis of Distinct and Co-existing Transcriptional Programs Regulating Tumor Dormancy

调节肿瘤休眠的不同和共存转录程序的功能分析

• 批准号: 10584353
• 负责人: Maria Sosa
• 金额: $ 38.43万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584353
• 关键词: Address; Agonist; Bar Codes; Biological Markers; Biology; Bone Marrow; COUP transcription factor I; Cancer Etiology; Cancer Relapse; Cell Cycle Arrest; Cell Survival; Cessation of life; ChIP-seq; Chromatin; Clinical; Clinical Trials; Data; Detection; Disease; Disease Progression; Disease remission; Distant; Endowment; Enhancers; Frequencies; Genes; Genetic Transcription; Goals; Grant; Head and Neck Squamous Cell Carcinoma; Heterogeneity; Human; Individual; Knowledge; LIF gene; Lung; Malignant Neoplasms; Malignant neoplasm of prostate; Metastatic Prostate Cancer; Modeling; Molecular; Monitor; Neoplasm Metastasis; Organ; Organ Culture Techniques; Pathway interactions; Patients; Phase; Population; Prevalence; Prevention; Primary Neoplasm; Proliferating; Protocols documentation; Publishing; Recurrence; Regulation; Relapse; Reporting; Repression; Research; Residual Neoplasm; Risk Factors; Role; STAT3 gene; Sampling; Signal Transduction; Technology; Testing; Therapeutic; Time; Tretinoin; Tumor Cell Biology; Validation; Work; cancer cell; cell behavior; chemotherapy; chromatin remodeling; conventional therapy; design; gain of function; insight; loss of function; lymph nodes; malignant breast neoplasm; mortality; neoplastic cell; oncostatin M; pluripotency; predictive marker; prevent; programs; response; stem-like cell; therapeutic development; therapy design; transcription factor; transcriptome sequencing; treatment response; tumor

Presence of disseminated tumor cells (DTCs) following successful treatment of primary tumors poses a risk factor for metastasis which is the leading cause of cancer mortality. However, current knowledge on mechanisms controlling the state of DTCs (persistent dormancy vs. reactivation) is limited. Only detailed knowledge of DTC biology will open therapeutic alternatives which will extend remission. We demonstrated that the transcription factor NR2F1/COUP-TFI triggers the dormancy phase of DTCs in head and neck squamous cell carcinoma (HNSCC) by regulating the retinoic acid pathway and inducing a long-lasting cell cycle arrest. Here we present new preliminary data showing that the dormant HNSCC DTC population is heterogeneous and that the pluripotency gene SOX2 is upregulated in a subpopulation of DTCs that co-exist with, but are distinct from, NR2F1+ dormant DTCs in the lungs and lymph nodes. SOX2 maintains the dormancy of DTCs by upregulating LIF (leukemia inhibitory factor) and OSM (oncostatin M) signaling and by repressing retinoic acid- and MYC-related genes. In addition, the SOX2-driven dormancy program involves chromatin remodeling and appears to dictate a much shorter dormancy phase that facilitates higher metastasis initiating capacity (reactivation). We hypothesize that SOX2-induced dormancy is enabled via enhancer regulation and LIF/OSM signaling which facilitates greater reactivation potential and metastasis-initiating capacity than the less reactivation prone NR2F1+ DTCs. We also propose that a persistent state of dormancy with lower reactivation potential can be induced in SOX2+ DTCs by inducing NR2F1 activity. Lastly, we propose that SOX2+ DTCs can be selectively targeted by chemotherapy due to their higher reactivation rate. The specific aims of this study are: SA1. To identify the mechanism of dormancy and the reactivation rate controlled by SOX2 in DTCs. We will identify and functionalize the transcriptional targets of SOX2 (including LIF/OSM) in controlling the dormancy and rate of reactivation by using ChIP-Seq analysis, gain and loss of function, lung-explant organ culture model, and validation in human biospecimens. SA2. To determine whether SOX2+ dormant DTCs can be targeted to inhibit their reactivation or eliminated. We will determine 1- whether SOX2-driven dormancy program can be converted into an NR2F1- driven program with low reactivation potential by using protocols to induce NR2F1 activity and 2- whether SOX2+ DTCs can be selectively targeted by chemotherapy due to their higher reactivation rate, compared to NR2F1+ DTCs by using cellular barcoding and clonal tracking technology. Our long-term objective is to identify predictive biomarkers of the DTC status (dormant vs proliferating) and to gain insight necessary for therapeutic strategies to either maintain DTCs in a stable dormancy phase or induce their eradication.

成功治疗后，存在分散的肿瘤细胞（DTC） 肿瘤是转移的危险因素，这是癌症死亡率的主要原因。但是，当前 关于控制DTC状态（持续性休眠与重新激活）机制的知识是有限的。仅有的 DTC生物学的详细知识将开放治疗替代方案，以扩展缓解。 我们证明了转录因子NR2F1/COUP-TFI触发DTC的休眠阶段 通过调节视黄酸途径并诱导头颈部鳞状细胞癌（HNSCC） 持久的细胞周期停滞。在这里，我们提供新的初步数据，显示休眠的HNSCC DTC 种群是异质的，多能基因SOX2在DTC的亚群中上调 该与肺部和淋巴结中的NR2F1+休眠DTC相互共存。 Sox2保持 通过上调LIF（白血病抑制因子）和OSM（OSM）（OSM）（oncostatin M）信号的休眠，以及通过 抑制视黄酸和与MYC相关的基因。此外，SOX2驱动的休眠计划涉及 染色质重塑，并且似乎决定了一个短得多的休眠期，从而促进了更高的转移 引发能力（重新激活）。 我们假设SOX2诱导的休眠是通过增强剂调节和LIF/OSM信号启用的 与易于重新激活相比 NR2F1+ DTC。我们还建议，持续的休眠状态具有较低的重新激活潜力的可能是 通过诱导NR2F1活性在SOX2+ DTC中诱导。最后，我们建议Sox2+ DTC可以选择性地 由于其更高的重新激活率而被化学疗法靶向。这项研究的具体目的是： SA1。确定DTC中SOX2控制的休眠机理和重新激活率。我们 在控制休眠时，将识别并功能化SOX2（包括LIF/OSM）的转录目标 通过使用CHIP-seq分析，功能的增益和丧失，肺部器官培养模型的重新激活速率， 和人类生物测量的验证。 SA2。确定SOX2+休眠DTC是否可以针对抑制其重新激活或 淘汰。我们将确定1- SOX2驱动的休眠程序是否可以转换为NR2F1- 通过使用方案诱导NR2F1活性和2- SOX2+是否具有低重新激活电位的驱动程序 与NR2F1+相比 DTC通过使用蜂窝条形码和克隆跟踪技术。 我们的长期目标是确定DTC状态的预测生物标志物（休眠与增殖） 并获得治疗策略所必需的见解，以使DTC保持在稳定的休眠阶段或 诱导他们的根除。