Functional Determinants of Metastatic Dormancy

转移休眠的功能决定因素

• 批准号: 10428636
• 负责人: Julio A. Aguirre-Ghiso
• 金额: $ 61.06万
• 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/10428636
• 关键词: Adopted; Affect; Aftercare; Aging; Alveolar Macrophages; Automobile Driving; BMP7 gene; Bone Marrow; Breast; CSPG4 gene; Cancer Model; Cancer Patient; Carcinoma; Cell Survival; Clinical Trials; Cues; Data; Epigenetic Process; Evolution; Genes; Genetic Transcription; Goals; Hematopoietic stem cells; Homeostasis; Hypoxia; Impairment; Inflammatory; Link; Lung; Malignant Neoplasms; Mediating; Mesenchymal; Mesenchymal Stem Cells; Metastatic Neoplasm to the Bone; Metastatic Neoplasm to the Lung; Methods; Monitor; Mus; Neoplasm Metastasis; Organ; Primary Lesion; Primary Neoplasm; Proteins; Publishing; Relapse; Residual Cancers; Signal Transduction; Site; Systemic disease; TGFB2 gene; Testing; Therapeutic; Tissues; Tretinoin; Up-Regulation; WNT5A gene; age effect; aged; cancer cell; cancer therapy; cue reactivity; imprint; macrophage; malignant breast neoplasm; nestin protein; novel; pluripotency; prevent; programs; rational design; response; stem cell function; stem cell niche; therapy development; tumor hypoxia

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.

概括。大多数癌症患者死于源自传播癌细胞的转移 （DCC），几年和几十年后。这与DCC在休眠状态中生存的能力有关 状态和逃避疗法。我们的长期目标是将DCC的休眠视为全身性疾病 针对它们并防止继电器的机制。我们的总体假设是完整的机制 在原发性病变中的基因程序和目标器官利基信号之间，汇合以指导DCC 目标器官通过静止，多能和生存计划进入休眠。我们进一步假设 可以操纵这种信号来抑制转移。使用上皮癌模型，我们有 发现早期传播产生了间充质样（M样）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激活DCC前体启用DCC前体 静止计划并在目标器官中进入休眠。重要的是，也类似于M的早期DCC前体 表现出强烈的缺氧反应。发现早期和晚期DCC对视黄酸Wnt5a响应 BMP7和TGF2信号衍生自基质靶器器官。这些激活的转录程序 由ZFP281（一种新型的早期DCC休眠器调节剂）和NR2F1整合以诱导休眠状态。我们的新目标 以这些发现为基础并探索三个重要的新发现：1）早期和晚期缺氧信号 原发性病变打开静态程序，表观遗传印记DCC前体进入休眠 当它们到达目标器官时，2）到达骨髓（BM）的早期或晚期DCC进入休眠 对由Nestin+/Ng2+间充质干细胞（N+MSC）产生的TGF2和BMP7的响应，该响应 造血干细胞（HSC）休眠；在这些MSC中丧失N+MSC或TGF2表达导致骨骼 转移和3），在肺中，早期和晚期DCC居住在肺泡精心策划的亲遗物壁cc 巨噬细胞（AMS），当耗尽觉醒的休眠DCC时。我们建议研究来自 原发性病变缺氧以及BM和肺稳态壁ches已整合以保持DCC休眠状态。这 具体目的是：目标1。确定缺氧素质DCC如何休眠。目标2。确定如何 NG2+/Nestin+ MSC编排休眠壁ni，以及衰老如何影响这些机制。目标3。 确定组织居民如何肺肺泡巨噬细胞（AMS）决定DCC命运以及衰老如何影响 这些利基的功能。我们的建议将整合主要病变（早期或晚期）如何预编程DCC 对于定义的目标器官壁ni的休眠 受衰老的影响。这种方法将有助于设计理性方法以预测休眠开始，监视 残留癌症并开发疗法以诱导和维持休眠或放射线最小残留癌症。