Abstract B04: Exploring the roles of bone marrow adipocytes in metabolic adaptation of metastatic prostate tumors in bone

Abstract

Abstract Bone is a very common site of metastasis from prostate cancer (PCa). Over 70% of PCa patients after radical prostatectomy show evidence of disseminated tumor cells in their bone marrow and more than 80% of patients with recurrent PCa have signs of skeletal disease. Despite numerous advancements that have been made in detection and treatment of PCa in the recent years, there has been no measurable improvement in outcome for men with metastatic disease. To design effective therapies for this devastating and incurable disease we need to understand the molecular mechanisms that drive tumor cell adaptation and survival in the bone metastatic niche. Adipocytes are a major component of bone marrow stroma and their numbers greatly increase with age and obesity. They are metabolically active cells with specialized functions of storing and secreting fatty acids and adipokines, and influencing neighboring cells by a number of mechanisms. We have shown recently that marrow adiposity is an important factor in adaptation and progression of PCa tumors in the bone marrow microenvironment. Our data demonstrated that growth and invasion of PCa cells in vitro and in vivo is driven by lipid trafficking between bone marrow adipocytes and cancer cells and involves upregulation of lipid transporter fatty acid binding protein 4 (FABP4), pro-inflammatory interleukin IL1β, and oxidative stress protein Heme Oxygenase, a process that can be blocked by FABP4 inhibition. We have also shown that FABP4 expression is high in xenograft and patient prostate bone metastasis tissues and that its interaction with PPARγ is a potential driving mechanism of metastatic tumor growth in bone. Our present investigations are based on the hypothesis that metastatic tumor cells in the bone have to adapt their metabolism to take advantage of available sources of energy provided by the host cells. Using in vitro co-culture systems of marrow adipocytes with prostate tumor cells we demonstrate that tumor cells utilize fatty acids generated by adipocyte-driven lipolysis to sustain their growth and invasiveness. Stimulation of adipocyte lipolysis with β3-adrenergic receptor agonist isoproterenol leads to further increase in FABP4 and IL1β expression in tumor cells, a result confirming involvement of those two factors in adipocyte-driven behavior in bone. Examination of RNA and protein expression of acetyl-CoA carboxylase (ACC) and carnitine palmitoyltransferase 1 (CPT1) reveals adaptation of tumor lipid metabolism via modulation of β-oxidation pathways. In addition, our results show that tumor cells upregulate their own monoacylglycerol lipase (MAGL), result suggesting lipid remodeling by tumor cells. Collectively our results demonstrate that bone marrow adipocytes serve as energy source for metastatic PCa cells. Lipidomic analyses and studies utilizing adipocyte-specific deletion of lipolytic enzymes such as ATGL are currently ongoing. These studies have a potential to reveal how marrow adipocytes influence prostate tumor metabolism and lead to unraveling of unique therapeutic targets for treatment of this presently incurable metastatic disease. Citation Format: Mackenzie K. Herroon, Erandi Rajagurubandara, Aimalie L. Hardaway, Izabela Podgorski. Exploring the roles of bone marrow adipocytes in metabolic adaptation of metastatic prostate tumors in bone. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B04. doi:10.1158/1538-7445.CHTME14-B04