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.
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.
|Lu, Songjian; Cai, Chunhui; Yan, Gonghong et al. (2016) Signal-Oriented Pathway Analyses Reveal a Signaling Complex as a Synthetic Lethal Target for p53 Mutations. Cancer Res 76:6785-6794|
|Carroll, Brittany L; Pulkoski-Gross, Michael J; Hannun, Yusuf A et al. (2016) CHK1 regulates NF-ÎºB signaling upon DNA damage in p53- deficient cells and associated tumor-derived microvesicles. Oncotarget 7:18159-70|
|Xu, Ruijuan; Wang, Kai; Mileva, Izolda et al. (2016) Alkaline ceramidase 2 and its bioactive product sphingosine are novel regulators of the DNA damage response. Oncotarget 7:18440-57|
|GarcÃa-Barros, MÃ³nica; Coant, Nicolas; Kawamori, Toshihiko et al. (2016) Role of neutral ceramidase in colon cancer. FASEB J 30:4159-4171|
|McCracken, A N; McMonigle, R J; Tessier, J et al. (2016) Phosphorylation of a constrained azacyclic FTY720 analog enhances anti-leukemic activity without inducing S1P receptor activation. Leukemia :|
|Adada, Mohamad; Luberto, Chiara; Canals, Daniel (2016) Inhibitors of the sphingomyelin cycle: Sphingomyelin synthases and sphingomyelinases. Chem Phys Lipids 197:45-59|
|Espaillat, Mel Pilar; Kew, Richard R; Obeid, Lina M (2016) Sphingolipids in neutrophil function and inflammatory responses: Mechanisms and implications for intestinal immunity and inflammation in ulcerative colitis. Adv Biol Regul :|
|Wang, K; Xu, R; Snider, A J et al. (2016) Alkaline ceramidase 3 deficiency aggravates colitis and colitis-associated tumorigenesis in mice by hyperactivating the innate immune system. Cell Death Dis 7:e2124|
|Kitatani, K; Usui, T; Sriraman, S K et al. (2016) Ceramide limits phosphatidylinositol-3-kinase C2Î²-controlled cell motility in ovarian cancer: potential of ceramide as a metastasis-suppressor lipid. Oncogene 35:2801-12|
|Wu, Song; Powers, Scott; Zhu, Wei et al. (2016) Substantial contribution of extrinsic risk factors to cancer development. Nature 529:43-7|
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