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.

原发性肿瘤成功治疗后出现播散性肿瘤细胞（dtc）