Bone is a preferential site of metastasis from prostate cancer (PCa). Age and obesity, conditions that increase adipocyte numbers in bone marrow, are risk factors for skeletal metastases from PCa. Marrow adipocytes are responsible for the secretion of a multitude of factors, such as lipids, cytokines, hormones, fatty acids, and glycerol, that have the propensity to influence neighboring cells. Our focus is on the interactions between adipocytes and tumor cells that have infiltrated the bone marrow. Specifically, we are examining how the secretion, transport, and uptake of adipocyte-supplied factors promote metastatic progression in bone. We have shown that PCa cells exposed to adipocytes undergo increased metabolic pressure towards glycolysis and lactic acid fermentation, a characteristic of the Warburg phenotype. We also demonstrated evidence of adipocyte-induced hypoxia signaling in tumor cells. Since it is well-established that both glycolysis and hypoxia can render tumor cells more aggressive and potentially more resistant to therapies, we hypothesize that adipocyte-supplied within the bone microenvironment cause a metabolic switch to glycolysis in PCa cells, leading to increased aggressiveness and survival of the metastatic tumor in the bone marrow niche. We will test this hypothesis through the following two aims: 1) establish the contribution of adipocyte- supplied lipids to metabolic changes in tumor cells; and 2) determine the adipocyte-induced changes in the PCa cell fatty acyl lipidome and identify key lipid metabolites contributing to altered tumor metabolism and hypoxia. We will utilize in vitro and in vivo models of marrow adiposity in combination with lipidomics technology to examine metabolic effects of adipocyte-tumor cell interactions in bone. The main focus of this proposed project is to elucidate novel mechanisms behind chemoresistance and sustained survival of metastatic PCa tumors in bone and to illuminate therapeutic targets for this presently incurable metastatic disease.
This application examines the interaction of bone marrow adipocytes and prostate cancer (PCa) cells that have metastasized to and infiltrated the bone marrow microenvironment. Studies planned include: determining the role of adipocyte-supplied lipids in regulation of the metabolic phenotype of PCa cells, examining how PCa cells influence the secretory phenotype of adipocytes; and characterizing the fatty acyl lipidome of tumor cells exposed to adipocytes that is associated with metabolic adaptation and survival in bone. This study will elucidate novel interactions between bone marrow adipocytes and PCa cells that affect tumor cell metabolism and potentially reveal novel therapeutic targets for treatment of this presently incurable disease.
