Epigenetic and microenvironmental regulation of dormant disseminated cancer

摘要：大多数HNSCC患者死于早期可能发生的局部复发和/或转移， 或在初次肿瘤切除后多年。这可能是由于残留的播散性肿瘤细胞(DTC)所致 病人处于休眠状态。在骨髓(BM)中可以检测到DTC，但很少会引起转移， 暗示这一地点处于休眠状态。我们发现HNSCC树突状细胞休眠先于转移 而休眠的DTC受独特的染色质状态和微环境线索的支配，这些微环境线索可以 源自血管壁龛。通过丧失功能的筛选，我们还发现了染色质重构体 迫使肿瘤细胞休眠的物质。此外，利用我们从衰老模型中获得的信息，我们 确定休眠的DTCs表达在衰老细胞中发现的染色质调节器和分泌因子。 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的休眠状态期间，一个强有力的、但可逆的增长停止计划。我们发现， 静止和分化信号、维甲酸、转化生长因子-2和骨形态发生蛋白7可诱导休眠和 转移抑制。处于休眠状态的癌细胞也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(宏H_2A，夹杂的H3.3)上调 在分化、衰老和转移抑制过程中上调。此外，CRISPR-CAS9 屏幕显示染色质重构体ARID1A是休眠的执行者。我们建议 微环境调节因子和表观遗传调节因子共同诱导和维持休眠。我们将对此进行测试 A的假说)研究组蛋白变异体宏H_2A与静止和 DTC休眠诱导中的衰老程序，B)破译ARID1A如何执行休眠和C) 通过识别微环境信号诱导休眠所允许的染色质状态。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。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。这个 康迪利斯团队将提供最先进的活体成像来解剖表观遗传学和 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实验室将允许在人类DTC样本中验证我们的发现。这提供了一种 无与伦比的机会，剖析单个DTC休眠的微环境和表观遗传调节。

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.