Stem cell, tumor and bone marrow microenvironment cross-talk in vivo

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A growing body of evidence suggests that the host microenvironment plays an important role in the regulation of both normal and malignant stem cell self-renewal and differentiation. The specific locations, cellular components and molecular details of these stem cell niches are, however, little understood. Using in vivo confocal and multiphoton molecular imaging techniques to study cell interactions in the intact murine bone marrow (BM), we have defined a novel perivascular tumor and hematopoietic stem/progenitor cell (HSPC) niche. We have identified the molecules used by leukemic cells to access this niche, however the mechanisms governing HSC transit to these areas have not yet been defined. Moreover, the role of this niche in maintaining normal HSCs or coordinating specific HSC cell functions is unknown. Given the importance of HSC-based transplantation therapies as well as the clinical significance of tumor metastasis to the BM, there is great therapeutic potential in understanding these cellular interactions. The long-term goals of our research are, therefore, to define the molecular architecture and functional significance of this tumor and HSC niche using state-of-the-art in vivo imaging techniques combined with cell and molecular biology approaches. Specifically, we will 1) examine the mechanisms governing HSC transit and engraftment in these niches, 2) determine how tumor growth impacts the niche and whether tumor and benign HSCs compete within the niche, and 3) develop targeted nanoparticles to release encapsulated compounds in precise regions of the vascular niche. These nanoparticles will serve as a unique tool to elucidate the critical molecules that mediate HSC and tumor proliferation in the niche and as a prototype for a targeted drug delivery agent. Ultimately, we aim to use the knowledge from these studies to design specific anti-tumor treatments that spare normal hematopoiesis and to define factors that improve the efficacy of stem cell-based therapies.