The overall organizing hypothesis of this Program posits that bioactive sphingolipids function as important regulators of several key tumor cell attributes, including tumor initiation, differentiation, growth, apoptosis, senescence, inflammation, invasion, and metastasis. As a corollary, enzymes of sphingolipid metabolism are emerging as specific and novel targets in modulating these important cancer attributes. Unfortunately, the study of bioactive lipids is rife with complications, both conceptual and technical and thus the study of lipids necessitates the collaborative interactions of various disciplines and specialized cores. Thus, we have evolved 4 distinct projects that collaborate to investigate the overall hypothesis. These projects address highly interrelated metabolic pathways that converge on the Golgi apparatus. Each project has identified a key node in these pathways that constitutes a specific vulnerability in the target cancer under study. Thus, Project 1 will test and advance the hypothesis that the novel acid sphingomyelinase/ceramide kinase pathway defines a previously unappreciated mechanism regulating invasiveness and metastasis of breast cancer. Project 2 will test the hypothesis that alkaline ceramidase 2 is a novel tumor suppressor whose suppression promotes development and progression of hepatocellular carcinoma. Project 3 will test the hypothesis that sphingosine kinase 1 (SK1) is a therapeutic target for p53 null and mutant cancers, and that Ser/Gly deprivation can be harnessed therapeutically to degrade SK1 and lead to cancer cell death. Project 4 will test the hypothesis that sphingomyelin synthase 1 is an indispensable novel regulator of proliferation of GATA1-positive AMLs (including the poorly studied acute erythroid, M6 and megakaryocytic, M7 leukemias) and a potential novel target for improving the dismal therapeutic response of these leukemias. These 4 projects will be supported by two unique research cores: The Lipidomics Shared Resource which will provide advanced analytical lipid chemistry and flux analysis, and by a Sphingolipid Animal Cancer Pathobiology Shared Resource that focuses on mutants/knock outs in enzymes of sphingolipid metabolism and models of in vivo carcinogenesis. It has recently introduced biobanking and CRISPR-mediated nock outs. This Program group has been highly integrated and productive (having published in the past 5 years 76 manuscripts, 50 of which were in collaboration) and has advanced significantly our understanding of sphingolipids (one of the last frontiers of basic research) in caner biology and therapeutics. We are now poised to advance pre-clinical studies and translational research based on our understanding of these novel pathways. These studies continue to identify novel targets and strategies for cancer therapeutics.
The studies proposed in this program project aim at defining how specific pathways of lipid (fat) metabolism and specific enzymes in these pathways regulate key functions of cancer cells. These include the production of factors that regulate the ability of the tumor cells to migrate and invade; pathways that regulate responses to DNA damage, mechanisms of cancer cell viability and death, pathways of cancer differentiation and senescence. These pathways are turning out to have key functions in the regulation of cancer growth, invasion, differentiation, and metastasis. Understanding these novel pathways and mechanisms not only enhances our understanding of cancer behavior, but also promises to lead us to the identification of novel targets for developing new inhibitors of cancer by focusing on specific enzymes (ceramide kinase, alkaline ceramidase, sphingosine kinase, and sphingomyelin synthase). The study of sphingolipids is very difficult and highly specialized, yet very promising for cancer research. Our program brings together several investigators with complementary and overlapping interests and expertise. We have also developed two unique shared resources; an Animal cancer pathology core and a lipidomics core.
|Bai, Aiping; Bielawska, Alicja; Rahmaniyan, Mehrdad et al. (2018) Dose dependent actions of LCL521 on acid ceramidase and key sphingolipid metabolites. Bioorg Med Chem 26:6067-6075|
|Newcomb, Benjamin; Rhein, Cosima; Mileva, Izolda et al. (2018) Identification of an acid sphingomyelinase ceramide kinase pathway in the regulation of the chemokine CCL5. J Lipid Res 59:1219-1229|
|Espaillat, Mel Pilar; Snider, Ashley J; Qiu, Zhijuan et al. (2018) Loss of acid ceramidase in myeloid cells suppresses intestinal neutrophil recruitment. FASEB J 32:2339-2353|
|Hannun, Yusuf A; Obeid, Lina M (2018) Sphingolipids and their metabolism in physiology and disease. Nat Rev Mol Cell Biol 19:175-191|
|Schwartz, Nicholas U; Linzer, Ryan W; Truman, Jean-Philip et al. (2018) Decreased ceramide underlies mitochondrial dysfunction in Charcot-Marie-Tooth 2F. FASEB J 32:1716-1728|
|Moorthi, Sitapriya; Burns, Tara Ann; Yu, Gui-Qin et al. (2018) Bcr-Abl regulation of sphingomyelin synthase 1 reveals a novel oncogenic-driven mechanism of protein up-regulation. FASEB J 32:4270-4283|
|Morris, Thomas G; Borland, Samantha J; Clarke, Christopher J et al. (2018) Sphingosine 1-phosphate activation of ERM contributes to vascular calcification. J Lipid Res 59:69-78|
|Coant, Nicolas; García-Barros, Mónica; Zhang, Qifeng et al. (2018) AKT as a key target for growth promoting functions of neutral ceramidase in colon cancer cells. Oncogene 37:3852-3863|
|Ren, Jihui; Snider, Justin; Airola, Michael V et al. (2018) Quantification of 3-ketodihydrosphingosine using HPLC-ESI-MS/MS to study SPT activity in yeast Saccharomyces cerevisiae. J Lipid Res 59:162-170|
|Shimizu, Yoshiko; Furuya, Hideki; Tamashiro, Paulette M et al. (2018) Genetic deletion of sphingosine kinase 1 suppresses mouse breast tumor development in an HER2 transgenic model. Carcinogenesis 39:47-55|
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