MICROENVIRONMENTAL CONTROLS OF TUMOR DORMANCY

肿瘤休眠的微环境控制

• 批准号: 9897506
• 负责人: Sheila A Stewart
• 金额: $ 50.39万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9897506
• 关键词: Age; Aging; Automobile Driving; Bone Marrow; Breast Cancer Cell; Breast Cancer Patient; Cancer Relapse; Cell Proliferation; Cells; Cessation of life; Clinic; Depressed mood; Development; Diagnosis; Distant; Early Diagnosis; Genetic; Growth; IL6 gene; Immune response; Immune system; Knowledge; Lesion; Life; Location; Malignant Neoplasms; Mesenchymal; Mesenchyme; Metastatic Neoplasm to the Bone; Modeling; Molecular; Mus; Neoplasm Metastasis; Osteoblasts; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmacology; Phenotype; Play; Process; Production; Proliferating; Quality of life; Recurrence; Relapse; Risk Factors; Role; Signal Transduction; Site; Sleep; Stromal Cells; Testing; Therapeutic; Time; Work; bone; bone cell; bone turnover; cancer recurrence; cell growth; chemotherapy; human tissue; mRNA Expression; mRNA Stability; malignant breast neoplasm; mouse model; neoplastic cell; new therapeutic target; novel; novel therapeutics; palliative; senescence; side effect; single-cell RNA sequencing; therapy outcome; tumor; tumorigenesis

Bone metastasis is a key determinant of long-term survival and quality of life for breast cancer patients. Despite the fact that the majority of breast cancer cases are diagnosed early, approximately 10-20% recur in patients previously “cured”, demonstrating that primary disseminated tumor cells (DTCs) metastasize early and remain dormant in distant sites only to awaken years later. Indeed, approximately 50% of patients harbor DTCs in their bone marrow and among metastatic sites, bone metastasis is the most common site and correlates with reduced survival and quality of life. Given the large percentage of patients who return to the clinic years after their initial “cure”, and the sad fact that treatment options are limited or only palliative, uncovering the mechanisms that protect dormant DTCs and allow their eventual outgrowth will have a profound impact on the development of novel therapies and patient outcome. We have developed a novel genetic mouse model (FASST) to spatially and temporally control the activation of senescence in mesenchymal cells including osteoblasts in the bone. Using the FASST model, we found that the activation of senescence led to increased expression of the protumorigenic senescence associated secretory phenotype (SASP) in bone mesenchymal cells that drove local bone turnover and facilitated tumor DTC proliferation in the bone. Intriguingly, we found that DTCs localized near senescent cells, raising the possibility that the niche created by these cells drove DTCs to proliferate. Because months to years can pass between an initial diagnosis and relapse, the fact that senescent cells increase in human tissue over this time frame and we that find that senescent cells drive DTC proliferation, we hypothesize that activation of senescence in the bone mesenchyme instigates emergence from dormancy and growth into overt metastatic bone lesions. To test this hypothesis, we propose to establish the functional impact of bone turnover and SASP on dormant DTC dynamics and determine how depletion of senescent osteoblasts impact DTC dormancy within the bone. We will also ask how dormant DTCs interact with the bone and how this is altered upon the activation of senescence. We will also ask if an aging immune system contributes to emergence of DTCs from dormancy. Finally, we will carry out single cell RNA sequencing of DTCs isolated from the bone +/- activation of senescence to determine how extrinsic signals from the bone impact DTC intrinsic pathways. Together these approaches will poise us to develop novel therapies that target the bone stromal compartment while simultaneously attacking entrenched DTCs.

骨转移是乳腺癌患者长期生存和生活质量的关键决定因素。 尽管大多数乳腺癌病例都是早期诊断的，但在乳腺癌患者中约有10-20%复发。 先前“治愈”的患者，表明原发性播散性肿瘤细胞（DTC）早期转移， 在遥远的地方休眠，数年后才苏醒。事实上，大约50%的患者 在骨髓和转移部位中，骨转移是最常见的部位， 与生存率和生活质量下降相关。鉴于大部分患者返回 在他们最初的“治愈”后的几年里，以及治疗选择有限或仅治标不治本的可悲事实， 揭示保护休眠DTC并允许其最终发展的机制， 对新疗法的发展和患者结局产生深远影响。我们已经开发出一种新颖 遗传小鼠模型（FASST）在空间和时间上控制衰老的激活， 间充质细胞，包括骨中的成骨细胞。使用FASST模型，我们发现， 衰老导致促肿瘤衰老相关分泌表型表达增加 （SASP）在骨髓间充质细胞中驱动局部骨转换并促进肿瘤DTC增殖， 骨头有趣的是，我们发现DTCs位于衰老细胞附近，这增加了小生境 由这些细胞产生的细胞驱动DTC增殖。因为从最初的一次到现在的一次 诊断和复发，事实上，衰老细胞在人体组织中增加，在这段时间内， 发现衰老细胞驱动DTC增殖，我们假设骨中衰老的激活 间充质促使从休眠中出现并生长成明显的转移性骨病变。为了验证这一 假设，我们建议建立骨转换和SASP对休眠DTC的功能影响 动力学，并确定衰老成骨细胞的消耗如何影响骨内DTC的休眠。我们 还将询问休眠的DTC如何与骨骼相互作用，以及在激活后如何改变。 衰老我们还将询问老化的免疫系统是否有助于DTC从休眠中出现。 最后，我们将对从骨+/-活化的 衰老，以确定来自骨的外在信号如何影响DTC内在途径。综合这些 方法将使我们能够开发针对骨基质室的新疗法， 同时攻击根深蒂固的DTC。