(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: 9262173
• 负责人: Charles P. Lin
• 金额: $ 55.37万
• 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/9262173
• 关键词: Ablation; Acute Myelocytic Leukemia; Address; Aftercare; Animals; Blocking Antibodies; Blood Circulation; Blood specimen; Bone Marrow; Bone structure; CXCR4 gene; Cancer Relapse; Cell Cycle; Cells; Cellular biology; Characteristics; Collaborations; Discontinuous Capillary; Endosteum; Event; Flow Cytometry; G0 Phase; Gene Deletion; Genetic; Growth; Hematologic Neoplasms; Hematopoietic stem cells; Hypoxia; Imaging technology; Individual; Laboratories; Lasers; Lead; Leukemic Cell; Leukemic Hematopoietic Stem Cell; Link; Location; Malignant Neoplasms; Methods; Microdissection; Microscopy; Molecular; Monitor; Mus; Osteoblasts; Oxygen; Pharmacology; Predisposition; Recurrence; Research; Resolution; Seeds; Solid Neoplasm; Source; Techniques; Therapeutic; Time; Treatment outcome; Work; arteriole; bone imaging; cancer cell; cell type; cellular imaging; chemotherapy; experimental study; image guided; in vivo; interdisciplinary approach; intravital microscopy; leukemia; mouse model; neoplastic cell; nestin protein; novel; phosphorescence; prevent; public health relevance; response; sensor; 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（应用程序提供）：该提案旨在解决挑衅性问题PQC-2：哪些分子或细胞事件在治疗后会产生肿瘤休眠，什么导致复发？我们将通过检查骨髓（BM）来解决这个问题，骨髓（BM）不仅为血液学恶性肿瘤提供了有利的微环境，而且还为经常在该位置持续种植并持续存在的实体瘤细胞。这些细胞可以在长时间的明显不活跃后重新出现，并成为新的癌症生长的来源。了解休眠的调节方式对于制定旨在防止癌症缓解的治疗策略很重要。我们的中心假设是定位是休眠的重要决定因素。将正常造血干细胞（HSC）定位到BM中适当的壁ni，对于维持HSC的静止和长期功能至关重要。在这里，我们建议研究化学疗法后BM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在静态壁ches中定位恶性细胞来维持的，随后改变其​​定位的事件可以触发恶性细胞以退出其静止状态。通过跟踪 使用插入式显微镜在小鼠BM中表达新细胞周期荧光指示剂的单个癌细胞，我们将确定静态壁nir的位置，其中维持细胞的位置 在G0状态。我们将通过使用两光子磷光寿命显微镜（2PLM）绘制BM中局部氧浓度（2PLM）的局部氧浓度，并通过激光显微解剖和捕获RNA-SEPAR的NICHE细胞来鉴定利基特异性分子表达。最后，我们将检查小众成分的遗传或药理操作是否会导致细胞定位，细胞周期状态的变化以及对化学疗法的易感性的改变。如果成功的话，这项工作可能会导致一种新的方法，将癌细胞通过靶向定位来使癌细胞对化疗。