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.

成功治疗原发性肿瘤后存在播散性肿瘤细胞 (DTC) 肿瘤构成转移的危险因素，而转移是癌症死亡的主要原因。然而，目前 关于控制 DTC 状态（持续休眠与重新激活）的机制的知识有限。仅有的 DTC 生物学的详细知识将开辟治疗替代方案，从而延长缓解期。 我们证明转录因子 NR2F1/COUP-TFI 触发 DTC 的休眠期 在头颈鳞状细胞癌 (HNSCC) 中通过调节视黄酸途径并诱导 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 群体是异质的，并且多能性基因 SOX2 在 DTC 亚群中上调 与肺和淋巴结中的 NR2F1+ 休眠 DTC 共存，但又不同。 SOX2 维持 通过上调 LIF（白血病抑制因子）和 OSM（制瘤素 M）信号传导以及通过 抑制视黄酸和 MYC 相关基因。此外，SOX2驱动的休眠程序涉及 染色质重塑，似乎决定了更短的休眠期，有利于更高的转移 启动能力（重新激活）。 我们假设 SOX2 诱导的休眠是通过增强子调节和 LIF/OSM 信号传导实现的 与不易再激活的细胞相比，这有利于更大的再激活潜力和转移启动能力 NR2F1+ 故障码。我们还建议，具有较低重新激活潜力的持久休眠状态可以是 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 由于其较高的再激活率而成为化疗的目标。本研究的具体目的是： SA1。确定 DTC 中 SOX2 控制的休眠机制和重新激活率。我们 将识别并功能化 SOX2（包括 LIF/OSM）控制休眠的转录靶标 使用 ChIP-Seq 分析、功能获得和丧失、肺外植体器官培养模型的再激活率， 并在人体生物样本中进行验证。 SA2。确定是否可以针对 SOX2+ 休眠 DTC 来抑制其重新激活或 被淘汰。我们将确定 1- SOX2 驱动的休眠程序是否可以转换为 NR2F1- 通过使用协议诱导 NR2F1 活性和 2- 是否 SOX2+ 驱动程序具有低再激活潜力 与 NR2F1+ 相比，DTC 的再激活率更高，因此可以通过化疗选择性地靶向 使用蜂窝条形码和克隆跟踪技术进行 DTC。 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） 并获得治疗策略所需的见解，以维持 DTC 处于稳定的休眠阶段或 促使它们被消灭。