Functional Determinants of Metastatic Dormancy

转移休眠的功能决定因素

• 批准号: 10516864
• 负责人: Julio A. Aguirre-Ghiso
• 金额: $ 40.76万
• 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: 2022-01-12 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10516864
• 关键词: Functional; Determinants; Metastatic; Dormancy

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.

总结。大多数癌症患者死于源自播散性癌细胞的转移。 (DCCs)，治疗后数年和数十年。这与DCC在休眠状态下存活的能力有关 状态和逃避治疗。我们的长期目标是将DCC的休眠理解为一种系统性疾病 有针对性的机制，防止复发。我们的首要假设是互补机制 在原发灶中的基因程序和靶器官生态位信号之间，融合以指示DCC 靶器官通过静止、多能和存活计划进入休眠状态。我们进一步假设 这样的信号可以被操纵来抑制转移。使用我们已有的上皮癌模型 发现早期扩散会产生间充质样(M样)休眠乳腺癌(BC)DCC。 我们还发现，晚期原发肿瘤中的缺氧可以激活DCC前体 静止程序并进入目标器官的休眠状态。重要的是，类似M的早期DCC前兆也 表现出强烈的缺氧反应。早期和晚期DCC均对维甲酸、Wnt5A、 BMP7和转化生长因子-2信号来源于基质靶器官壁龛。它们激活转录程序 ZFP281(一种新的DCC早期休眠调节剂)与NR2F1整合，诱导休眠。我们的新目标 在这些发现的基础上，探索三个重要的新发现：1)早期和晚期的缺氧信号 原发病变启动静息程序，表观遗传学印记DCC前体进入休眠 当它们到达靶器官时，2)早或晚到达骨髓(BM)的DCC进入休眠状态 Nestin+/Ng2+间充质干细胞对转化生长因子-2和骨形态发生蛋白7的应答 造血干细胞处于休眠状态；N+间充质干细胞或转化生长因子-2表达缺失导致成骨 3)在肺部，早期和晚期的DCC存在于由肺泡编排的促休眠的壁龛中。 巨噬细胞(AM)，当耗尽时唤醒休眠的DCC。我们建议研究信号是如何从 原发灶缺氧与骨髓和肺内环境平衡相结合，使DCC处于休眠状态。这个 具体目标是：目标1.确定低氧如何启动DCC的休眠。目标2.确定如何 NG2+/Nestin+MSCs协调休眠生态位，以及衰老如何影响这些机制。目标3. 确定组织驻留的肺泡巨噬细胞(AM)如何决定DCC的命运以及衰老如何影响DCC的 这些壁龛的功能。我们的建议将整合原发病变(早期或晚期)如何预先规划DCC 在确定的目标器官利基中休眠，这可以通过特定的提示进一步加强休眠，这可能是 受衰老的影响。这种方法将有助于设计合理的方法来预测休眠开始、监控 并开发治疗方法，以诱导和维持休眠或根除微小的残留癌症。