Yusuf A. Hannun, MD
Our laboratory is focused on studies on bioactive lipids, with a special emphasis on sphingolipids. These studies have allowed us to propose a critical role for sphingolipids in eukaryotic stress responses. We are interested in understanding how sphingolipid metabolism is regulated under various conditions and in response to extracellular stimuli. We are also interested in defining the functions of bioactive sphingolipids, including sphingosine and ceramide. We perform our studies in human cancer cells as well as in yeast as a model organism.
Chiara Luberto, PhD
Research in my lab focuses on regulation of sphingolipid signaling and the impact that its dysregulation might have on certain diseases, such as specific types of cancers. In particular, we focus on the study of the mammalian enzymes sphingomyelin synthases (SMS1 and SMS2) and their regulation of lipid mediated signaling through controlling the levels of ceramide and diacylglycerol (DAG). In fact, SMSs can directly regulate in opposing directions the levels of these two important bioactive lipids, which often exert opposing roles in the regulation of fundamental cellular functions such as protein trafficking/secretion, proliferation, differentiation and apoptosis.
The laboratory focuses on two main lines of research:
- The role of SMS1 and SMS2 in regulating DAG-mediated protein trafficking and secretion at the Trans Golgi Network (TGN) and the impact of such regulation on specific cargo molecules such as insulin and antimicrobial molecules.
- The role and function of SMS1 and SMS2 in the development and/or progression of cancer, in particular leukemias and lung cancer.
Cungui Mao, PhD
My research program is to understand how alkaline ceramidases regulate the metabolism of bioactive sphingolipids and how this regulation in turn influences biological responses, including tumorigenesis, inflammation, angiogenesis, and stress responses.
It has been well established that sphingolipid metabolites, ceramide, sphingosine, and sphingosine-1-phosphate (S1P) act as signaling molecules that mediate various cellular responses. It is generally believed that ceramide and sphingosine mediate cell proliferation inhibition, differentiation, and apoptosis whereas S1P promotes cell proliferation and survival, so the relative cellular levels of these sphingolipids may determine a cell’s fate, to proliferate and survive or to undergo growth arrest and die. In addition, S1P has been implicated in various biological processes, such as cardiovascular development, angiogenesis, immunity, neurogenesis, and tumorigenesis. Because these bioactive lipids are interchangeable, regulation of a single step in their metabolic pathway may systematically alter their cellular levels, thus influencing various biological responses.
My group was the first to identify and clone three human alkaline ceramidases (ACER1, ACER2, and ACER3), the enzymes that catalyze the hydrolysis of ceramides into sphingosine, which in turn is phosphorylated to from S1P. As implied in their names, these enzymes have alkaline pH optima for their activity. Both ACER1 and ACER2 require calcium for their activity, and ACER3, which has basal activity, is significantly activated by calcium. They share a high degree of similarity in protein sequence but are distinct in substrate specificity, cellular localization, and tissue distribution. ACER1 hydrolyzes ceramides with unsaturated long or very long acyl chains, ACER3 ceramides with unsaturated long acyl chains, and ACER2 most mammalian ceramide species. ACER1 is localized to the endoplasmic reticulum (ER) whereas both ACER2 and ACER3 are localized to both the ER and Golgi complex. ACER1 is highly expressed in specific tissues, such as the skin, whereas both ACER2 and ACER3 are ubiquitously expressed. ACER3 is expressed at much higher levels in most tissues than ACER1 or ACER2. Our compelling data suggest that these ACER ceramidases have distinct roles in regulating the metabolism of bioactive sphingolipids and biological responses likely due to their distinct substrate specificity and tissue expression specificity.
Christopher Clarke, PhD
Deregulation of cellular sphingolipid levels has been found to occur in many cancers but it it is unknown if this dysregulation helps to drive tumorigenesis, and the factors that cause this dysregulation are unclear. This lack of a mechanistic understanding of how sphingolipids are coupled to tumor behavior remains a critical barrier that has contributed in part to a long-delayed translation of sphingolipid metabolism as an effective druggable target for cancer. To address this knowledge gap, the overarching goal of my research program is to develop a mechanistic understanding of the interplay between oncogenes and SL metabolism, how this functionally couples to tumorigenesis, and how this can be exploited therapeutically. This would be used to guide the development of anti-cancer drugs targeting ‘tumor-type’ specific sphingolipid metabolism, an attractive approach as most metabolic outputs are enzymatically driven and such enzymes are highly druggable.
At present, I have two major research projects:
1. Oncogenic reprogamming of sphingolipid metabolism as a driver of anoikis resistance and metastasis
2. Targeting sphingolipid metabolism to reduce doxorubicin cardiotoxicity without interfering with its anti-cancer effects.