OVERVIEW

Lay Summary

My laboratory studies a family of natural lipids called sphingolipids that control cell growth and immune functions in humans and other living organisms. We have found that sphingolipids can influence the development and progression of cancer, and that certain sphingolipids found in foods such as soy are able to prevent cancer formation. We also find that sphingolipids can help to stimulate the growth and movement of tissue stem cells and can thereby influence the ability of certain tissues to recover from injury. Our studies are exploring strategies to modulate sphingolipid signaling pathways in ways that will promote immune responses, tissue stem cell functions and tissue regeneration and prevent or reverse cancer development and progression.

Scientific Overview

Functions of S1P in human physiology & pathophysiology

My laboratory is focused on elucidating the biological activities of the signaling lipid sphingosine-1-phosphate (S1P) and related molecules in relation to developmental biology, human physiology and disease. We pay particular attention to the functions of the enzyme S1P lyase, which is responsible for regulating S1P signaling pools. We have three major research programs underway in the laboratory. 1) Our major program is focused on clarifying the role(s) of S1P, S1P lyase and other sphingolipids in cancer biology and treatment. We have found that endogenous S1P signaling pathways promote colon cancer development in several mouse models of the disease. These effects can be attributed to S1P-mediated activation of key inflammatory signaling pathways, leading to induction of microRNA molecules that promote inflammation and cell transformation. In contrast, dietary sphingolipids called sphingadienes inhibit intestinal tumor development and are cytotoxic to many pediatric and adult cancer cell types. Sphingadienes act by inhibiting key cancer signaling pathways including those involving AKT and WNT. We are developing sphingadienes as a novel cancer treatment for pediatric and adultcancers. By investigating the impact of S1P on gene expression patterns, we have recently discovered a novel sphingolipid-regulated oncogene that has a powerful effect on the growth of colon, prostate and neuroblastoma cells in vitro and in vivo. The interaction of this oncogene product with cell cycle inhibitors may underlie its effect on cancer cells and tumors. 2) Our second scientific program arose from our observation that fruitfly S1P lyase mutants develop a progressive myopathy. This led us to develop a research program focused on elucidating the role of S1P signaling in muscle regeneration and muscle stem cell functions. Our recent findings demonstrate that S1P activates muscle stem cells and facilitates regeneration of injured and dystrophic muscle through a S1PR2/STAT3-dependent signaling pathway that suppresses p21 and p27. Modulation of the pathway by blocking S1P degradation using chemical inhibitors of S1P lyase promotes regeneration in dystrophic mice. 3) Lastly, we have generated conditional mouse models lacking S1P lyase function in specific tissue compartments. Using these models, we are dissecting the role of S1P lyase in lymphocyte trafficking and other aspects of lymphocyte development and function.

Revised: Thursday, April 26, 2012 3:49 PM