Functional Determinants of Metastatic Dormancy

摘要大多数癌症患者死于源自播散性癌细胞的转移 （DCC），治疗后数年和数十年。这与DCC在休眠状态下生存的能力有关。 陈述和逃避治疗。我们的长期目标是了解作为一种系统性疾病的DCC休眠 针对他们并防止复发的机制。我们的总体假设是， 原发性病变和靶器官生态位信号中的基因程序之间的关系，收敛到指导DCC在 靶器官通过静止、多能性和存活程序进入休眠。我们进一步假设 这些信号可以被操纵来抑制转移。使用上皮癌模型， 发现早期传播产生间充质样（M样）休眠乳腺癌（BC）DCC。 我们还发现，在晚期原发性肿瘤中，缺氧可以使DCC前体活化， 静止程序并在靶器官中进入休眠。重要的是，M样早期DCC前体也 表现出强烈的缺氧反应发现早期和晚期DCC都对维甲酸、WNT 5A、 BMP 7和TGF β 2信号来源于基质靶器官小生境。这些激活转录程序 ZFP 281（一种新的DCC早期休眠调节剂）和NR 2F 1整合诱导休眠。我们的新目标 在这些发现的基础上，探索了三个重要的新发现：1）早期和晚期缺氧信号 原发病变开启静止程序，表观遗传印记DCC前体进入休眠 当它们到达靶器官时，2）到达骨髓（BM）的早期或晚期DCC在 巢蛋白+/NG 2+间充质干细胞（N+ MSC）产生的TGF β 2和BMP 7的反应，这些细胞控制 造血干细胞（HSC）休眠;在这些MSC中的N+ MSC或TGF β 2表达的丧失导致骨 转移和3），在肺，早期和晚期DCC驻留在由肺泡 巨噬细胞（AM），当耗尽唤醒休眠的DCC。我们打算研究来自 原发性病变缺氧沿着BM和肺稳态小生境被整合以保持DCC休眠。的 具体目标是：目标1。确定缺氧如何使DCC休眠。AIM 2.确定如何 NG 2 +/Nestin+ MSC协调休眠壁龛以及衰老如何影响这些机制。AIM 3. 确定组织驻留肺泡巨噬细胞（AM）如何决定DCC的命运以及衰老如何影响DCC。 这些小生境的功能。我们的建议将整合原发性病变（早期或晚期）如何预编程DCC 对于在限定的目标器官小生境中的休眠，其通过特定的线索进一步加强休眠， 受老化影响。这种方法将有助于设计合理的方法来预测休眠开始，监测 并开发治疗方法以诱导和维持休眠或根除最小残留癌症。

SUMMARY. The majority of cancer patients die of metastases originating from disseminated cancer cells (DCCs), years and decades after treatment. This has been linked to the ability of DCCs to survive in a dormant state and evade therapies. Our long-term goal is to understand dormancy of DCCs as a systemic disease mechanism to target them and prevent relapse. Our overarching hypothesis is that complementary mechanism between gene programs in primary lesions and target organs niche signals, converge to instruct DCCs in target organs to enter dormancy via quiescence, pluripotency and survival programs. We further hypothesize that such signals can be manipulated to suppress metastasis. Using epithelial cancer models we have discovered that early dissemination spawns mesenchymal-like (M-Like) dormant breast cancer (BC) DCCs. We also discovered that hypoxia in advanced primary tumors can prime DCC precursors to activate quiescence programs and enter dormancy in target organs. Importantly, M-like early DCC precursors also display a strong hypoxia response. Both early and late DCCs were found to respond to retinoic acid, WNT5A, BMP7 and TGF2 signals derived from stromal target organ niches. These activate transcriptional programs integrated by ZFP281 (a novel early DCC dormancy regulator) and NR2F1 to induce dormancy. Our new aims build on these findings and explore three significant new discoveries: 1) Hypoxia signals in early and late primary lesions turn on quiescence programs that epigenetically imprint DCC precursors to enter dormancy when they arrive to target organs, 2) early or late DCCs that arrive to the bone marrow (BM) enter dormancy in response to TGF2 and BMP7 produced by Nestin+/NG2+ mesenchymal stem cells (N+MSCs), which control hematopoietic stem cells (HSCs) dormancy; loss of N+MSCs or TGF2 expression in these MSCs led to bone metastasis and 3), in lungs, early and late DCCs reside in pro-dormancy niches orchestrated by alveolar macrophages (AMs), which when depleted awaken dormant DCCs. We propose to study how signals from primary lesion hypoxia along with BM and lung homeostatic niches are integrated to keep DCCs dormant. The specific aims are: AIM 1. Determine how hypoxia primes DCCs for dormancy. AIM 2. Determine how NG2+/Nestin+ MSCs orchestrate dormancy niches and how aging affects these mechanisms. AIM 3. Determine how tissue resident lung alveolar macrophages (AMs) dictate DCC fate and how aging impacts the function of these niches. Our proposal will integrate how primary lesions (early or late) may pre-program DCCs for dormancy in defined target organ niches which further reinforce dormancy via specific cues, which may be affected by aging. This approach will aid the design of rational methods to predict dormancy onset, monitor residual cancer and develop therapies to induce and maintain dormancy or eradicate minimal residual cancer.