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: Project 1 will address the specific hypothesis that acid sphingomyelinase defines a novel pathway of cancer cell biology involving two specific mediators, the chemokine RANTES and the cytokine IL6, with important roles in cancer inflammation and metastasis. Project 2 will test the specific hypothesis that alkaline ceramidase 1 acts as a tumor suppressor in non-melanoma skin cancers and its downregulation promotes skin tumorigenesis by stimulating hyperproliferation of epidermal keratinocytes. Project 3 will test the hypothesis that loss of Sphingosine Kinase 1 is a key event in mediating the tumor suppressor effects of P53, especially on the induction of senescence. Project 4 will test the hypothesis that BCR-ABL1 transcriptionally regulates SMS1 and that elevated SMS1 activity sustains the tumorigenic potential of BCR-ABL1 positive cells. These 4 projects will be supported by two unique research cores: The Lipidomics Core which will provide analytical and synthetic lipid chemistry, and by a Sphingolipid Animal Cancer Pathobiology Core that focuses on mutants/knock outs in enzymes of sphingolipid metabolism and models of in vivo carcinogenesis. This Program group has been highly integrated and productive 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.

Public Health Relevance

The Program focuses on the study of novel molecules that derive from the metabolism of fat molecules present in the cell. We have been working on discovering these molecules, how they work, and what they do in the regulation of cancer cell growth, aging, and metastasis. We bring together 4 highly collaborative groups that work closely with each other with a primary focus on understanding the pathways that regulate these molecules and their functions in human cancer. We particularly aim at defining vulnerable points in these pathways as novel targets for the development of rational and new therapies. We have also developed two outstanding shared resources that support these projects and many other investigators across the nation: a lipid core focused on developing novel molecules and on measuring the various lipid molecules, and an animal pathobiology core that allows us to begin translating our novel results into specific human diseases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA097132-15
Application #
9550922
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Arya, Suresh
Project Start
2002-07-01
Project End
2019-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
15
Fiscal Year
2018
Total Cost
Indirect Cost
Name
State University New York Stony Brook
Department
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
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
Carroll, Brittany L; Bonica, Joseph; Shamseddine, Achraf A et al. (2018) A role for caspase-2 in sphingosine kinase 1 proteolysis in response to doxorubicin in breast cancer cells - implications for the CHK1-suppressed pathway. FEBS Open Bio 8:27-40
Xu, Ruijuan; Garcia-Barros, Monica; Wen, Sally et al. (2018) Tumor suppressor p53 links ceramide metabolism to DNA damage response through alkaline ceramidase 2. Cell Death Differ 25:841-856
Coant, Nicolas; Hannun, Yusuf A (2018) Neutral ceramidase: Advances in mechanisms, cell regulation, and roles in cancer. Adv Biol Regul :
Trayssac, Magali; Hannun, Yusuf A; Obeid, Lina M (2018) Role of sphingolipids in senescence: implication in aging and age-related diseases. J Clin Invest 128:2702-2712
Munshi, Mansa A; Gardin, Justin M; Singh, Ashutosh et al. (2018) The Role of Ceramide Synthases in the Pathogenicity of Cryptococcus neoformans. Cell Rep 22:1392-1400

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