(PQC2) Localization as a determinant of cancer dormancy

(PQC2) 定位作为癌症休眠的决定因素

• 批准号: 8876904
• 负责人: Charles P. Lin
• 金额: $ 54.7万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-18 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8876904
• 关键词: Ablation; Acute Myelocytic Leukemia; Address; Aftercare; Animals; Blocking Antibodies; Blood Circulation; Blood specimen; Bone Marrow; CXCR4 gene; Cancer Relapse; Cell Cycle; Cells; Characteristics; Collaborations; Discontinuous Capillary; Endosteum; Event; Flow Cytometry; G0 Phase; Gene Deletion; Genetic; Growth; Hematologic Neoplasms; Hematopoietic; Hematopoietic stem cells; Hypoxia; Image; Imaging technology; Individual; Laboratories; Lead; Leukemic Cell; Life; Link; Location; Malignant Neoplasms; Maps; Methods; Microscopy; Molecular; Monitor; Mus; Osteoblasts; Oxygen; Predisposition; Recurrence; Research; Resolution; Seeds; Solid Neoplasm; Source; Staging; Structure; Techniques; Therapeutic; Time; Treatment outcome; Work; arteriole; cancer cell; cell type; cellular imaging; chemotherapy; image guided; in vivo; interdisciplinary approach; intravital microscopy; laser capture microdissection; leukemia; mouse model; neoplastic cell; nestin protein; novel; phosphorescence; prevent; public health relevance; research study; response; sensor; stem cell biology; time use; tool; transcriptome sequencing; tumor; two-photon

 DESCRIPTION (provided by applicant): This proposal aims to address the provocative question PQC- 2: What molecular or cellular events establish tumor dormancy after treatment and what leads to recurrence? We will address this question by examining the bone marrow (BM), a location known to provide a favorable microenvironment not only for hematologic malignancies, but also for solid tumor cells that frequently seed and persist in this location. These cells can reemerge after prolonged periods of apparent inactivity and become the source of new cancer growth. Understanding how dormancy is regulated is important for developing therapeutic strategies that aim to prevent cancer relapse. Our central hypothesis is that localization is an important determinant of dormancy. Localization of normal hematopoietic stem cells (HSCs) to proper niches in the BM is critical for maintaining quiescence and long-term function of the HSC. Here we propose to investigate the relationship between dormancy and localization of malignant cells in the BM following chemotherapy. We hypothesize that dormancy is maintained by localization of malignant cells in quiescent niches, and subsequent events that alter their localization can trigger the malignant cells to exit their quiescent state. By tracking individual cancer cells expressing a novel cell cycle fluorescent indicator in the mouse BM using intravital microscopy, we will identify the location of quiescent niches where cells are maintained in the G0 state. We will examine the link between quiescence and hypoxia by mapping local oxygen concentration in the BM with high spatial resolution using two-photon phosphorescence lifetime microscopy (2PLM), and identify niche-specific molecular expression by laser microdissection and capturing of niche cells for RNA-seq. Finally, we will examine if genetic or pharmacologic manipulations of the niche components can result in altered cellular localization, changes in cell cycle status, and susceptibility to chemotherapy. If successful, this work can lead to a new way of sensitizing cancer cells to chemotherapy by targeting their localization.

 描述（由申请人提供）：该提案旨在解决 PQC-2 这一具有争议性的问题：哪些分子或细胞事件在治疗后建立肿瘤休眠以及哪些导致复发？我们将通过检查骨髓 (BM) 来解决这个问题，众所周知，骨髓 (BM) 不仅为血液恶性肿瘤提供有利的微环境，而且还为经常在该位置播种和持续存在的实体瘤细胞提供有利的微环境。这些细胞在长时间明显不活动后可以重新出现，并成为新的癌症生长的来源。了解休眠是如何调节的对于制定旨在预防癌症复发的治疗策略非常重要。我们的中心假设是定位是休眠的重要决定因素。正常造血干细胞 (HSC) 定位到 BM 中的适当位置对于维持 HSC 的静止和长期功能至关重要。在这里，我们建议研究化疗后骨髓中恶性细胞的休眠与定位之间的关系。我们假设休眠是通过将恶性细胞定位在静止状态来维持的，并且随后改变其​​定位的事件可以触发恶性细胞退出其静止状态。通过追踪 使用活体显微镜在小鼠骨髓中表达新型细胞周期荧光指示剂的单个癌细胞，我们将确定细胞维持的静止生态位的位置 处于G0状态。我们将通过使用双光子磷光寿命显微镜 (2PLM) 以高空间分辨率绘制 BM 中的局部氧浓度来检查静止和缺氧之间的联系，并通过激光显微切割和捕获小生境细胞进行 RNA 测序来识别小生境特异性分子表达。最后，我们将检查利基成分的遗传或药理学操作是否会导致细胞定位的改变、细胞周期状态的变化以及对化疗的敏感性的改变。如果成功，这项工作可以带来一种通过靶向癌细胞定位来使癌细胞对化疗敏感的新方法。