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.

总结：大多数HNSCC患者死于局部复发和/或转移，这些复发和/或转移可能发生在早期， 或原发肿瘤切除后多年。这可能是由于残留的播散性肿瘤细胞（DTC） 潜伏在病人体内DTC可以在骨髓（BM）中检测到，但很少引起转移， 说明这里处于休眠状态我们发现HNSCC DTCs的休眠先于转移 休眠的DTC由独特的染色质状态和微环境线索控制， 源自血管龛。通过功能丧失筛选，我们还确定了染色质重塑 促使肿瘤细胞休眠。此外，利用我们从衰老模型中获得的信息，我们 确定休眠DTC表达染色质调节因子和衰老细胞中发现的分泌因子。 我们假设，特定的微环境线索和表观遗传调节诱导和维持 一个强大的，但可逆的，在DTC的休眠状态生长停滞程序。我们发现 休眠和分化信号，视黄酸（atRA），TGF β 2和BMP 7可以诱导休眠， 转移抑制食管癌细胞还显示出全面的抑制性染色质状态， 特异性转录因子（NR 2F 1）和组蛋白变体（macroH 2A，剪切H3.3）的上调，发现 在分化、衰老和转移抑制期间上调。CRISPR-Cas9 筛选鉴定了染色质重塑剂ARID 1A作为休眠的执行者。我们建议 微环境和表观遗传调节剂会聚以诱导和维持休眠。我们将测试这个 A）研究与静止相关的组蛋白变体macroH 2A的作用， DTC休眠诱导中的衰老程序，B）破译ARID 1A如何强制休眠，以及C） 通过识别微环境信号诱导休眠的染色质允许状态。MPI SYNERGY：Aguirre-Ghiso和伯恩斯坦实验室沿着我们的合作者有着丰富的历史， 出版物和积极合作。这个团队在休眠，转移， 以及在癌症休眠和转移领域取得突破的染色质生物学。的 Condeelis团队将提供最先进的活体成像，以解剖表观遗传和 微环境调节DTC休眠开始和单细胞分辨率的存活。重要的是 Klein和Stoecklein实验室将允许在人类DTC样本中验证我们的发现。这提供了一 无与伦比的机会，解剖微环境和表观遗传调节单一DTC休眠。