(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.