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.

摘要：大多数癌症患者死于播散性癌细胞的转移。 （DCC），治疗后数年和数十年，这与 DCC 在休眠状态下的生存能力有关。 我们的长期目标是将 DCC 的休眠理解为一种全身性疾病。 我们的首要假设是互补机制。 原发性病变的基因程序和靶器官生态位信号之间，汇聚以指导 DCC 靶器官通过静止、多能性和生存程序进入休眠状态。 使用我们拥有的上皮癌模型可以操纵这些信号来抑制转移。 发现早期传播会产生间质样（M-Like）休眠乳腺癌（BC）DCC。 我们还发现，晚期原发性肿瘤中的缺氧可以促使 DCC 前体激活 重要的是，M 样早期 DCC 前体也参与其中。 发现早期和晚期 DCC 对视黄酸、WNT5A 均表现出强烈的缺氧反应。 来自基质靶器官生态位的 BMP7 和 TGF2 信号可激活转录程序。 由 ZFP281（一种新型早期 DCC 休眠调节剂）和 NR2F1 集成以诱导休眠。 基于这些发现并探索三个重要的新发现：1）早期和晚期的缺氧信号 原发性病变开启静止程序，通过表观遗传印记 DCC 前体进入休眠状态 当它们到达靶器官时，2) 到达骨髓 (BM) 的早期或晚期 DCC 进入休眠状态 对 Nestin+/NG2+ 间充质干细胞 (N+MSC) 产生的 TGF2 和 BMP7 的反应，控制 造血干细胞 (HSC) 休眠；这些 MSC 中 N+MSC 或 TGFβ2 表达的丧失导致骨形成 3)、在肺中，早期和晚期 DCC 驻留在由肺泡精心安排的促休眠生态位中 巨噬细胞 (AM)，当巨噬细胞耗尽时会唤醒休眠的 DCC，我们建议研究如何从巨噬细胞发出信号。 原发性病变缺氧与 BM 和肺稳态生态位相结合，使 DCC 保持休眠状态。 具体目标是： AIM 1. 确定缺氧如何促使 DCC 休眠。 AIM 2. 确定如何启动 DCC 休眠。 NG2+/Nestin+ MSC 协调休眠生态位以及衰老如何影响这些机制。 确定组织驻留肺泡巨噬细胞 (AM) 如何决定 DCC 命运以及衰老如何影响 我们的建议将整合原发性病变（早期或晚期）如何预编程 DCC。 用于在确定的目标器官生态位中休眠，通过特定线索进一步强化休眠，这可能是 这种方法将有助于设计合理的方法来预测休眠开始、监测。 残留癌症并开发诱导和维持休眠或根除微小残留癌症的疗法。