Benjamin Newcomb
B.S. Seattle University, 2005
9th Year MSTP
4th Year Molecular & Cellular Biology Graduate Student
Advisor: Dr. Yusuf A. Hannun, Director of the Stony Brook Cancer Center, Vice Dean for Cancer Medicine, Joel Kenny Professor of Medicine at Stony Brook University
Department: Medicine, Stony Brook University
Graduate Program: Molecular & Cellular Biology
Title: Sphingolipids in Breast Cancer Progression and Inflammatory Responses
Abstract:
Acid Sphingomyelianse (ASM) is a key regulatory enzyme that produces the bioactive lipid ceramide, which is converted into other sphingolipids by enzymes such as Ceramide Kinase (CERK). Previous literature has implicated ASM and CERK in inflammatory signaling, but the specific role of ASM and CERK as mediators of inflammatory signaling in breast cancer has remained elusive. In this work, we delineated the role of ASM in p38 activation and subsequent IL-6 production, as well as the role of CERK as a downstream effector of activated ASM. Since previous literature has shown that TNF-α induced dramatic alterations in the sphingolipid profile of cells, sphingolipidomic analysis was carried out on TNF-α treated MCF7 cells. The data revealed that TNF-α induced robust production of ceramide-1-phosphate (C-1-P) that accompanied an increase in CCL5. Given that previous literature showed CCL5 production is dependent on ASM, this data suggested that CERK may be acting downstream of ASM to produce C-1-P and induce CCL5. Indeed, siRNA ablation of CERK decreased CCL5 production. Furthermore, previous literature implicated C-1-P in Golgi localization of cPLA2. To define a role for ASM as an upstream modulator of CERK activity, the requirement for ASM in cPLA2 localization was tested. Ablation of ASM blocked cPLA2 localization to the Golgi network, suggesting ASM is acting upstream of CERK. Since ASM appeared to have Golgi specific functions, ASM mutants that accumulate in the Golgi network were tested for the ability to induce CCL5. We found that Golgi targeted ASM can induce CCL5 production. Taken together, these results demonstrate a role for CERK and C-1-P in CCL5 production and a role for ASM in modulation of CERK function. These results highlight the previously unappreciated role of C-1-P in CCL5 production and present new opportunities for targeting sphingolipid metabolism in treatment of breast cancers.
Publications:
(MSTP-supported publications indicated with an *)
*Newcomb B, Rein C, Obeid LM, Hannun Y. Identification of an Acid Sphingomyelinase Ceramide Kinase Pathway in the Regulation of the Chemokine CCL5. Prepared for submission.
*Chen JY, Newcomb B, Zhou C, Pondick JV, Ghoshal S, York SR, Motola DL, Coant N, Yi JK, Mao C, Tanabe KK, Bronova I, Berdyshev EV, Fuchs BC, Hannun Y, Chung RT, Mullen AC. Tricyclic Antidepressants Promote Ceramide Accumulation to Regulate Collagen Production in Human Hepatic Stellate Cells. Sci Rep. 2017 Mar 21;7:44867.
*Newcomb B, Hannun YA. Sphingolipids as Mediators of Breast Cancer Progression, Metastasis, Response and Resistance to Chemotherapy. Bioactive Sphingolipids in Cancer Biology and Therapy, Editors: Yusuf A. Hannun, Chiara Luberto, Cungui Mao, Lina Marie Obeid. Book 2015. ISBN: 978-3-319-20749-0.
*Bai A, Szulc ZM, Bielawski J, Pierce JS, Rembiesa B, Terzieva S, Mao C, Xu R, Wu B, Clarke CJ, Newcomb B, Liu X, Norris J, Hannun YA, Bielawska A. Targeting (cellular) lysosomal acid ceramidase by B13: design, synthesis and evaluation of novel DMG-B13 ester prodrugs. Bioorg Med Chem. 2014 Dec 15;22(24):6933-44. doi: 10.1016/j.bmc.2014.10.025. Epub 2014 Oct 22.
*Hannun YA, Newcomb B. A new twist to the emerging functions of ceramides in cancer: novel role for platelet acid sphingomyelinase in cancer metastasis. EMBO Mol Med. 2015 Apr 9;7(6):692-4. doi: 10.15252/emmm.201505161.
Wang J, Wegener JE, Huang TW, Sripathy S, De Jesus-Cortes H, Xu P, Tran S, Knobbe W, Leko V, Britt J, Starwalt R, McDaniel L, Ward CS, Parra D, Newcomb B, Lao U, Nourigat C, Flowers DA, Cullen S, Jorstad NL, Yang Y, Glaskova L, Vingeau S, Kozlitina J, Yetman MJ, Jankowsky JL, Reichardt SD, Reichardt HM, Gärtner J, Bartolomei MS, Fang M, Loeb K, Keene CD, Bernstein I, Goodell M, Brat DJ, Huppke P, Neul JL, Bedalov A, Pieper AA. Wild-type microglia do not reverse pathology in mouse models of Rett syndrome. Nature. 2015 May 21;521(7552):E1-4. doi: 10.1038/nature14444.
*Perry DM, Newcomb B, Adada M, Wu BX, Roddy P, Kitatani K, Siskind L, Obeid LM, Hannun YA, Defining a role for acid sphingomyelinase in the p38/interleukin-6 pathway. J Biol Chem, 2014. 289(32): p. 22401-12.
*Spincemaille P, Chandhok G, Newcomb B, Verbeek J, Vriens K, Zibert A, Schmidt H, Hannun YA, van Pelt J, Cassiman D, Cammue BP, Thevissen K, The plant decapeptide OSIP108 prevents copper-induced apoptosis in yeast and human cells. Biochim Biophys Acta, 2014. 1843(6): p. 1207-15.
*Montefusco DJ, Chen L, Matmati N, Lu S, Newcomb B, Cooper GF, Hannun YA, Lu X., Distinct signaling roles of ceramide species in yeast revealed through systematic perturbation and systems biology analyses. Sci Signal, 2013. 6(299): p. rs14.
*Montefusco DJ, Newcomb B, Gandy JL, Brice SE, Matmati N, Cowart LA, Hannun YA., Sphingoid bases and the serine catabolic enzyme CHA1 define a novel feedforward/feedback mechanism in the response to serine availability. J Biol Chem, 2012. 287(12): p. 9280-9.
Newcomb, B. and A. Bedalov, Identification of inhibitors of chromatin modifying enzymes using the yeast phenotypic screens. Methods Mol Biol, 2009. 548: p. 145-60.
Thaminy S, Newcomb B, Kim J, Gatbonton T, Foss E, Simon J, Bedalov A., Hst3 is regulated by Mec1-dependent proteolysis and controls the S phase checkpoint and sister chromatid cohesion by deacetylating histone H3 at lysine 56. J Biol Chem, 2007. 282(52): p. 37805-14.
