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.
We will examine the characteristics of the bone marrow that makes it a favorable microenvironment not only for hematologic malignancies such as leukemia, 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.
