Kazuaki Takabe, MD, PhD, FACS, FSSO

Our laboratory focuses on three main themes:

1. The role of sphingosine-1-phosphate (S1P) in cancer progression
2. Development of animal models that mimic human cancer progression
3. The role of bile acid signaling in cell metabolism and cancer

S1P is a signaling lipid mediator, which is generated inside the cells by sphingosine kinases, exported out of the cells, then bind and signal through five S1P specific G-protein coupled receptors (S1PR1-5), coined “inside-out signaling’ (Takabe K et al, Pharmacological Reviews 2008, Takabe K et al, Journal of Lipid Research 2014). Given that S1P cause cell survival, proliferation, migration and angiogenesis, we hypothesized that S1P play critical roles in cancer progression. We found that S1P is exported via multidrug resistant protein, ABC transporter C1 and G2, which implicate that those transporters resist to drugs not only because they secrete out drug compounds, but also export S1P that biologically worsen cancer cells (Takabe K et al, Journal of Biological Chemistry 2010). We found that Spinster 2 also exports S1P and regulates lymphatic network development in the lymph nodes (Nagahashi M et al, FASEB Journal 2013) and play critical roles in inflammatory diseases (Donoviel MS et al, FASEB Journal 2015). These findings led us to investigate the roles of S1P in tumor microenvironment, and found that S1P promote not only angiogenesis, but also lymphangiogenesis and lymph node metastasis of breast cancer (Nagahashi M et al, Cancer Research 2012). We also found that S1P levels are high in breast cancer compared from the surrounding normal breast tissue (Nagahashi M et al, Journal of Surgical Research 2016) that associate with sphingosine kinase 1 activity of human breast cancer (Tsuchida J et al, Journal of Surgical Research 2016). We invented a method that identified that S1P levels are high not only in breast cancer cells, but also in interstitial fluid that forms tumor microenvironment (Nagahashi M et al, Journal of Mammary Gland Biology and Neoplasia 2016). We found that another ABC transporter, C11, export S1P and are associated with worse survival (Yamada A et al, Breast Cancer Research and Treatment 2013). Further, we discovered that S1P link inflammation and caner in colitis-associated colon cancer model (Liang J et al, Cancer Cell 2013). We also found that S1P phosphatase 2 promotes disruption of colonic mucosal integrity in inflammatory bowel disease (Huang WC et al, FASEB Journal 2016). In breast cancer, we found that obesity worsen breast cancer via S1P production (Hait NC et al, Oncogenesis 2015). Intracellularly, we found that LPA1 upregulate sphingosine kinase 1 (Shida D et al, Cancer Research 2008) via ERK1-dependent manner (Ramachandran S et al, FEBS Letter 2010), and S1P play an essential role in IL-1 induced CXCL10 and CCL5 production (Harikumar KB et al, Nature Immunology 2014).

We have established a technique to generate syngeneic murine metastatic breast cancer model that mimic human breast cancer progression (Rashid OM et al, Breast Cancer Research and Treatment 2014). Utilizing this model, we found that the benefit of removal of the primary breast cancer in Stage IV disease depend upon the tumor burden (Rashid OM et al, Surgery 2013), and we also found that the lung metastasis model by tail vein injection of cancer cells is genetically similar to lung metastasis tumor from breast tumor (Rashid OM et al, Journal of Thoracic Disease 2013). Further, we have improved this model to be used for testing immunotherapy (Katsuta E et al, Journal of Surgical Research 2016). We also developed a syngeneic murine metastatic colon cancer model that metastasizes to lymph node before causing bowel obstruction or carcinomatosis (Terracina KP et al Journal of Surgical Research 2015).

We found that conjugated bile acids bind to S1P Receptor 2 (S1PR2) and signal through ERK (Studer E et al, Hepatology 2012). We further discovered that this bile acid signaling through S1PR2 and Sphingosine kinase 2 regulate lipid metabolism in hepatocytes (Nagahashi M et al, Hepatology 2015), thus play a role in development of Non-Alcoholic Fatty Liver Disease (Hylemon P et al, Hepatology 2016).