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: 10525056
• 负责人: Julio A. Aguirre-Ghiso
• 金额: $ 15.09万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-11 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10525056
• 关键词: Epigenetic; microenvironmental; regulation; dormant; disseminated

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患者死于可能发生的局部回报和/或转移， 或去除原发性肿瘤后的许多年。这可能是由于剩余的散布肿瘤细胞（DTC） 患者休眠。可以在骨髓（BM）中检测到DTC，但很少引起转移， 暗示该站点处于休眠状态。我们发现HNSCC DTC的休眠状态先于转移 休眠的DTC受独特的染色质状态和微环境线索的控制 源自血管生态位。通过功能丧失屏幕，我们还确定了染色质远程 强迫肿瘤细胞休眠。此外，使用我们从感应模型中得出的信息，我们 确定休眠的DTC表达在感觉细胞中发现的染色质调节剂和分泌因子。 我们假设特定的微环境提示和表观遗传调节剂会影响和维持 在休眠DTC状态下，一个强大但可逆的逮捕计划。我们发现 静止和分化信号，视黄酸（ATRA），TGF2和BMP7可以诱发休眠和 抑制转移。休眠的癌细胞还显示全球反射性染色质状态和 发现特定转录因子（NR2F1）和组蛋白变体（MacroH2a，剪切H3.3）的上调，发现 在分化，感应和转移抑制期间上调。此外，CRISPR-CAS9 筛选将染色质重塑剂ARID1A鉴定为休眠的执行者。我们提出了这一点 微环境和表观遗传调节剂会汇聚以诱导和保持休眠状态。我们将测试这个 假设通过a）研究与静止和 DTC休眠诱导中的感应程序，b）解密ARID1A如何执行休眠和C） 通过鉴定微观信号的染色质允许状态诱导休眠状态。 MPI 协同作用：Aguirre-Ghiso和Bernstein Labs以及我们的合作者有富有成效的历史 出版物和积极合作。该团队拥有休眠，转移的专业专业知识， 和染色质生物学，在癌症的休眠和转移领域取得了突破。 Condeelis团队将提供最先进的浸润成像，以剖析表观遗传和 DTC休眠发作和单细胞分辨率下存活的微环境调节。重要的是， 克莱因（Klein）和斯托克林（Stoecklein）实验室将允许在人类DTC样品中验证我们的发现。这提供了 剖析单个DTC休眠的微环境和表观遗传调节的无与伦比的机会。

项目成果

5-Azacytidine- and retinoic-acid-induced reprogramming of DCCs into dormancy suppresses metastasis via restored TGF-β-SMAD4 signaling.

• DOI: 10.1016/j.celrep.2023.112560
• 发表时间: 2023-06-27
• 期刊: Cell reports
• 影响因子: 8.8

How dormant cancer persists and reawakens.

• DOI: 10.1126/science.aav0191
• 发表时间: 2018-09-28
• 期刊: Science (New York, N.Y.)
• 作者: Aguirre-Ghiso JA