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MICROENVIRONMENTAL CONTROLS OF TUMOR DORMANCY

肿瘤休眠的微环境控制

基本信息

批准号：
10376279
负责人：
Sheila A Stewart
金额：
$ 49.7万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10376279
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

项目摘要

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。