Bone metastases are a frequent complication of certain malignancies, including advanced stage prostate cancer. The current body of literature suggests that metastatic prostate cancers progress in regions of the bone marrow that normally support hematopoietic stem cells (HSCs), termed 'niches.' Though the signaling mechanisms involved in metastatic prostate cancer cell (MPCC) engraftment have been elucidated, no study to date has defined the molecular mechanisms underlying MPCC progression in the bone marrow. We propose here a study that will identify and functionally validate the cell-surface and diffusible molecules produced by the bone marrow that are involved in MPCC progression in bones. For our proposed study, we will use our lab's previously described ectopic bone marrow niche assay in which we can: (a) establish an HSC- and MPCC-supportive ectopic bone marrow niche upon transplantation of highly purified 'parental' osteoblastic murine cells under the renal capsule of a recipient mouse and (b) further fractionate the 'parental' population using a variety of surface markers into distinct osteoblastic subsets that differentially support HSC self-renewal and MPCC proliferation. We first propose an in situ histological study to observe the locations of MPCCs in relation to our distinct osteoblastic cellular populations. From these observational studies, we will gain insight into which osteoblastic cellular subsets may engage in direct cell-cell interactions with MPCCs (i.e. cells in close proximity) and which distinct osteoblastic populations may engage in diffusible interactions with MPCCs (i.e. cells not in close proximity). We will next identify cell surface and secreted molecules expressed by our distinct osteoblastic subsets that are involved in MPCC proliferation dynamics using microarray gene expression analyses and multiplexed immunoassays, respectively. To validate candidate factors in the context of our ectopic bone marrow niche, we will employ both in vitro and in vivo assays to confirm the role that a specific molecule(s) plays in MPCC proliferation dynamics in bones. Presently, bone metastases represent an incurable and often deadly stage of cancer progression, with current therapies often only offering palliative treatments. We propose here a highly translational study that will identify novel molecular interactions required for metastatic progression in bones that could potentially be exploited by future therapies.
Prostate cancer cells that have metastasized to bones are thought to progress in regions of the bone marrow that normally support hematopoietic stem cells (HSCs), termed 'niches.' This proposal aims to identify molecular factors that are produced by cells within the bone marrow niche that foster metastatic prostate cancer progression within osseous tissues.
