Epigenetic and microenvironmental regulation of dormant disseminated cancer

休眠播散性癌症的表观遗传学和微环境调控

• 批准号: 9502259
• 负责人: Julio A. Aguirre-Ghiso
• 金额: $ 42.81万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-07 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9502259
• 关键词: Affect; Area; BMP4; BMP7 gene; Biological Assay; Biology; Biosensor; Blood Vessels; Bone Marrow; CRISPR screen; Cancer Patient; Cells; ChIP-seq; Chromatin; Chromatin Remodeling Factor; Cleaved cell; Clinical; Clip; Collaborations; Cues; Data; Disease; Disseminated carcinoma; Epigenetic Process; Excision; Exhibits; Fibroblasts; Grant; Growth; Head and Neck Squamous Cell Carcinoma; Histones; Human; IL6 gene; In Vitro; Interleukin-1 beta; Link; Lung; Malignant Epithelial Cell; Malignant Neoplasms; Metastasis Suppression; Metastatic Melanoma; Metastatic to; Modeling; Mus; Mutate; Neoplasm Metastasis; Organ; Patients; Pattern; Primary Neoplasm; Publications; Recording of previous events; Recurrence; Regulation; Resolution; Role; Sampling; Signal Transduction; Site; Testing; Tretinoin; Tumor Cell Biology; Tumor Suppressor Proteins; Up-Regulation; Validation; Variant; adult stem cell; base; cancer cell; chromatin remodeling; epigenetic regulation; epigenome; epigenomics; histone modification; in vivo; intravital imaging; loss of function; neoplastic cell; overexpression; programs; prostate cancer cell; response; senescence; stem cell niche; transcription factor; transcriptome; transcriptome sequencing

SUMMARY: The majority of HNSCC patients die from local recurrences and/or metastasis that can occur early, or many years after primary tumor removal. This can be due to disseminated tumor cells (DTCs) remaining dormant in patients. DTCs can be detected in the bone marrow (BM), but rarely give rise to metastasis, suggesting a dormant state in this site. We discovered that dormancy of HNSCC DTCs precedes metastasis and that dormant DTCs are governed by unique chromatin states and microenvironmental cues that can be derived from the vascular niche. Through loss-of-function screens, we also identified chromatin remodelers that enforce tumor cell dormancy. Further, using information we derived from senescence models, we determined that dormant DTCs express chromatin regulators and secreted factors found in senescent cells. We hypothesize that specific microenvironmental cues and epigenetic regulators induce and maintain a strong, yet reversible, growth arrest program during the dormant state of DTCs. We found that the quiescence and differentiation signals, retinoic acid (atRA), TGF2 and BMP7 can induce dormancy and metastasis suppression. Dormant cancer cells also display a global repressive chromatin state and upregulation of specific transcription factors (NR2F1) and histone variants (macroH2A, clipped H3.3), found upregulated during differentiation, senescence and metastasis suppression. In addition, CRISPR-Cas9 screens identified the chromatin remodeler ARID1A as an enforcer of dormancy. We propose that microenvironmental and epigenetic regulators converge to induce and maintain dormancy. We will test this hypothesis by A) investigating the role of histone variant macroH2A associated with quiescence and senescence programs in DTC dormancy induction, B) deciphering how ARID1A enforces dormancy and C) by identifying chromatin permissive states for dormancy induction by microenviromental signals. MPI SYNERGY: The Aguirre-Ghiso and Bernstein labs along with our collaborators have a productive history of publications and active collaborations. This team possesses specialized expertise in dormancy, metastasis, and chromatin biology that has delivered breakthroughs in the cancer dormancy and metastasis fields. The Condeelis team will provide the most advanced intravital imaging to dissect the epigenetic and microenvironmental regulation of DTC dormancy onset and survival at single cell resolution. Importantly, the Klein and Stoecklein labs will allow validation of our findings in human DTC samples. This provides an unsurpassed opportunity to dissect the microenvironmental and epigenetic regulation of single DTC dormancy.

摘要：大多数 HNSCC 患者死于早期发生的局部复发和/或转移， 或原发肿瘤切除多年后。这可能是由于残留的播散性肿瘤细胞 (DTC) 在患者体内处于休眠状态。 DTC 可在骨髓 (BM) 中检测到，但很少引起转移， 建议此站点处于休眠状态。我们发现 HNSCC DTC 的休眠先于转移 休眠 DTC 受到独特的染色质状态和微环境线索的控制，这些线索可以被 源自血管生态位。通过功能丧失筛选，我们还鉴定了染色质重塑者 强制肿瘤细胞休眠。此外，利用我们从衰老模型中获得的信息，我们 确定休眠的 DTC 表达衰老细胞中发现的染色质调节因子和分泌因子。 我们假设特定的微环境线索和表观遗传调节因子诱导和维持 在 DTC 休眠状态期间实施强力但可逆的生长抑制计划。我们发现 静止和分化信号，视黄酸（atRA）、TGFβ2和BMP7可以诱导休眠和 转移抑制。休眠癌细胞还表现出整体抑制染色质状态 发现特定转录因子 (NR2F1) 和组蛋白变体（macroH2A、剪切 H3.3）的上调 在分化、衰老和转移抑制过程中上调。此外，CRISPR-Cas9 筛选发现染色质重塑因子 ARID1A 是休眠的执行者。我们建议 微环境和表观遗传调节因子汇聚在一起诱导和维持休眠。我们将测试这个 假设 A) 研究组蛋白变体 MacroH2A 与静止相关的作用 DTC 休眠诱导中的衰老程序，B) 破译 ARID1A 如何强制休眠，C) 通过微环境信号识别休眠诱导的染色质许可状态。 MPI 协同效应：Aguirre-Ghiso 和 Bernstein 实验室以及我们的合作者拥有丰富的历史 出版物和积极的合作。该团队拥有休眠、转移、 和染色质生物学在癌症休眠和转移领域取得了突破。这 Condeelis 团队将提供最先进的活体成像来剖析表观遗传和 单细胞分辨率下 DTC 休眠开始和存活的微环境调节。重要的是， Klein 和 Stoecklein 实验室将验证我们在人类 DTC 样本中的发现。这提供了一个 这是剖析单个 DTC 休眠的微环境和表观遗传调控的绝佳机会。