Sarah Spiegel, PhD

Sphingosine-1-Phosphate: New Player in Immunity and Cancer

  • Ph.D., 1983, The Weizmann Institute of Science, Israel (Biochemistry)

  • 1982-1984, Dr. Chaim Weizmann Post-doctoral Fellowship for Scientific Research, NINDS, NIH, Bethesda, Maryland
  • 1985-1986, Visiting Associate, NINDS, NIH, Bethesda, Maryland


Our research is focused on the enigmatic lipid sphingosine-1-phosphate (S1P) whose role as a bioactive mediator in cell growth regulation was discovered in my lab nearly two decades ago (Nature, 365: 557, 1993). We also demonstrated that the dynamic balance between S1P and its precursors, sphingosine and ceramide, functions as a cellular rheostat that determines whether a cell survives or dies (Nature, 381: 800, 1996). Since then, there has been an explosion in the number of important physiological and pathophysiological processes in which S1P plays a key role, including cancer (cell growth, inhibition of apoptosis, angiogenesis, metastasis), the immune system (asthma, anaphylaxis, autoimmunity, sepsis, tissue rejection, atherosclerosis) and development (fertility, vascular maturation, cardiac, ear and brain development). The puzzle of how such a simple molecule as S1P can have such diverse roles has been resolved by our discovery that it functions not only inside cells but also as a ligand (agonist) for five specific cell-surface receptors (Nature Rev. Mol. Cell Biol. 4: 397, 2003). S1P is formed inside cells by two sphingosine kinases, SphK1 and SphK2, which we cloned and characterized, and can be exported out by specific transporters to activate its own receptors (PNAS 103:16394, 2006) in autocrine and/or paracrine manners (Science 291: 1800, 2001). This process that we call ‘inside-out signaling’ is important for many of the physiological and pathological actions of S1P (Cancer Cell 9: 148, 2006). More recently, we identified important direct intracellular targets of S1P. We showed that S1P produced by nuclear SphK2 binds to histone deacetylases and inhibits their activity, thus linking S1P and sphingolipid metabolism in the nucleus to gene expression and epigenetic regulation (Science 325: 1254, 2009). We also discovered that S1P is a missing essential cofactor for the ubiquitin ligase activity of tumor necrosis factor receptor associated factor 2 (TRAF2), uncovering a key role of SphK1 and S1P in cytokine signaling and NF-kappaB activation important in inflammatory, anti-apoptotic, and immune processes (Nature 465: 1084, 2010). Our lab found that SphK1/S1P axis drives a malicious amplification loop involving S1P receptor 1 and the NF-κB/IL-6/STAT3 pathway. This appears critical for progression from chronic inflammation to colon cancer (Cancer Cell 23, 107, 2013). Our research continues to be focused on the roles of S1P, the enzymes that regulate its levels (SphK1 and SphK2 and S1P phosphatases) as well as the S1P receptors and intracellular targets of S1P in physiology and pathophysiology.

View Dr. Spiegel's Publications via the National Library of Medicine's PubMed.
Sarah Spiegel, PhD
Professor and Chair
Mann T. and Sara D. Lowry Chair in Cancer Research
Dept. of Biochemistry & Molecular Biology
Virginia Commonwealth University
VCU Massey Cancer Center
PO Box 980614
MCV Campus
Sanger Hall, Room 2-011
1101 E. Marshall Street
Richmond, VA 23298-0614

  •      804-828-9330