cancer bioenergetics, nutrient transporter proteins, sphingolipids, cancer biology, metabolism, autophagy, Rab7, mTOR, Akt
1992 Membership in Phi Beta Kappa, Phi Kappa Phi, Golden Key, and Phi Sigma
1992 University Medalist for Class of 1992, UC Davis
1992-1994 Rhone-Poulenc Rorer Veterinary Scientist Training Program
1994-1999 NIH Medical Scientist Training Program
2000-2003 Helen Hay Whitney Postdoctoral Fellowship
2009 Chancellor’s Award for Excellence in Undergraduate Research
2014 UCI School of Biological Sciences Golden Apple teaching award
A resurgence of interest in cancer cell metabolism has led to the discovery that many oncogenes and tumor suppressor genes transform cells by altering cellular bioenergetics. While essential for oncogenesis, this metabolic reprogramming makes cancer cells exquisitely dependent upon a high rate of nutrient flux. This is a potential Achilles’ heel—constitutively-active oncogenes and the deletion of tumor suppressor genes prevent tumor cells from reducing biosynthesis and increasing catabolic reactions. Thus, cancer cells die when deprived of nutrients while normal cells become quiescent. My laboratory is taking a unique approach to fighting cancer by trying to exploit this difference by developing therapies that selectively starve cancer cells to death by down-regulating nutrient transporter proteins. Our immediate goal is to uncover the pathways that coordinately regulate mammalian nutrient transporter internalization and trafficking.
The "tumor suppressor lipid" ceramide is generated in response to almost all stresses encountered by cells. Ceramide can induce cell cycle arrest, differentiation, senescence and death. Moreover, many chemotherapeutics kill tumor cells by increasing ceramide levels. Precisely how ceramide limits cell growth and survival, however, has remained unclear. My lab has made a significant advance by establishing that ceramide induces severe bioenergetic stress secondary to nutrient transporter down-regulation. This model may help to explain why ceramide is more toxic to cancer cells than normal cells, how ceramide contributes to type 2 diabetes, and even how ceramide regulates cellular aging.
While it limits tumor cell growth and survival, ceramide has poor drug properties: it is extremely hydrophobic complicating delivery and is rapidly metabolized. To overcome these problems, my lab has developed water soluble and orally bioavailable sphingolipid-inspired small molecules through a collaboration with Dr. Stephen Hanessian's synthetic and medicinal chemistry group. These compounds inhibit tumor growth in prostate and colon cancer models with minimal toxicity to normal cells. Currently efforts in the lab are focused on pre-clinical evaluation of these compounds and on understanding their precise molecular mechanism of action.
Seong M. Kim, Saurabh G. Roy, Bin Chen, Tiffany M. Nguyen, Ryan J. McMonigle, Alison N. McCracken, Yanling Zhang, Satoshi Kofuji, Jue Hou, Elizabeth Selwan, Brendan T. Finicle, Tricia T. Nguyen, Archna Ravi, Manuel U. Ramirez, Tim Wiher, Garret G. Guenther, Mari Kono, Atsuo T. Sasaki, Lois S. Weisman, Eric O. Potma, Bruce J. Tromberg, Robert A. Edwards, Stephen Hanessian, Aimee L. Edinger (2016). Targeting cancer metabolism by simultaneously disrupting parallel nutrient access pathways. J Clin Invest. in press, Epub Sept 2016. doi:10.1172/JCI87148
McCracken AN, McMonigle RJ, Tessier J, Fransson R, Perryman MS, Chen B, Keebaugh A, Selwan E, Barr SA, Kim SM, Roy SG, Liu G, Fallegger D, Sernissi L, Brandt C, Moitessier N, Snider AJ, Clare S, Müschen M, Huwiler A, Kleinman MT, Hanessian S, Edinger AL (2016). Phosphorylation of a constrained azacyclic FTY720 analog enhances anti-leukemic activity without inducing S1P receptor activation. Leukemia. Epub 2016 Sep 30. doi:10.1038/leu.2016.244.
Perryman MS, Tessier J, Wiher T, O'Donoghue H, McCracken AN, Kim SM, Nguyen DG, Simitian GS, Viana M, Rafelski S, Edinger AL, Hanessian S. (2016) Effects of stereochemistry, saturation, and hydrocarbon chain length on the ability of synthetic constrained azacyclic sphingolipids to trigger nutrient transporter down-regulation, vacuolation, and cell death. Bioorg Med Chem. 2016 Sep 15;24(18):4390-7. doi: 10.1016/j.bmc.2016.07.038. Epub 2016 Jul 18. PMID: 27475534
Safaiyan S, Kannaiyan N, Snaidero N, Brioschi S, Biber K, Yona S, Edinger AL, Jung S, Rossner MJ, Simons M. (2016) Age-related myelin degradation burdens the clearance function of microglia during aging. Nat Neurosci. 2016 Aug;19(8):995-8. doi: 10.1038/nn.4325. PMID: 27294511
Walker WP, Oehler A, Edinger AL, Wagner KU, Gunn TM. (2016) Oligodendroglial deletion of ESCRT-I component TSG101 causes spongiform encephalopathy. Biol Cell. 2016 Jul 13. doi: 10.1111/boc.201600014. [Epub ahead of print] PMID: 27406702
Selwan E, Finicle BT, Kim SM, Edinger AL (2016). Attacking the supply wagons to starve cancer cells to death. FEBS Lett. 2016 Apr;590(7):885-907. doi: 10.1002/1873-3468.12121. Epub 2016 Mar 22. Review. PMID: 26938658
Chen B, Roy SG, McMonigle RJ, Keebaugh A, McCracken AN, Selwan E, Fransson R, Fallegger D, Huwiler A, Kleinman MT, Edinger AL and S Hanessian (2016). Azacyclic FTY720 Analogues that Limit Nutrient Transporter Expression but Lack S1P Receptor Activity and Negative Chronotropic Effects Offer a Novel and Effective Strategy to Kill Cancer Cells in vivo. ACS Chemical Biology, 11(2):409-14.
Pone EJ, Lam T, Edinger AL, Xu Z, and P Casali (2015). B Cell Rab7 Mediates Induction of AID Expression and Class-switching in T-dependent and T-independent Antibody Responses. Journal of Immunology 194:3065-78.
Fransson R, McCracken AN, Chen B, McMonigle RJ, Edinger AL and S Hanessian (2014). Design, Synthesis, and Anti-leukemic Activity of Stereochemically Defined Constrained Analogs of FTY720 (Gilenya). ACS Medicinal Chemistry Letters, published online Oct 10;4(10).
Garret G. Guenther*, Gang Liu*, Manuel U. Ramirez, Ryan J. McMonigle, Seong M. Kim, Alison N. McCracken, Yoosun Joo, Irina Ushach, Natalie L. Nguyen, and Aimee L. Edinger (2014). Loss of TSC2 confers resistance to ceramide and nutrient deprivation. Oncogene 33:1776-1787.
McCracken AN and Edinger AL (2013). Nutrient transporters: the Achilles' heel of anabolism. Trends in Endocrinology and Metabolism 24:200-8.
Saurabh Ghosh Roy, Michael W. Stevens, Lomon So, and Aimee L. Edinger (2013). Reciprocal effects of Rab7 deletion in activated and neglected T cells. Autophagy 9:1009-23.
Klionsky, D ... Edinger, AL ... and many other authors (2012). Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy. 8:445-544.
Chen J, Narayan SB, Edinger AL, Bennett MJ (2012). Flow injection tandem mass spectrometric measurement of ceramides of multiple chain lengths in biological samples. J Chromatogr B Analyt Technol Biomed Life Sci. 883-884:136-40.
Romero Rosales K, Singh G, Wu K, Chen J, Lilly MB, Peralta ER, Janes MR, Siskind LJ, Bennett MJ, Fruman DA, and AL. Edinger (2011). Sphingolipid-based drugs selectively kill cancer cells by down-regulating nutrient transporter proteins. Biochem J. 439(2):299-311.
Peralta EP, Martin BC, and AL Edinger (2010). TBC1D15 is a selective Rab7 GTPase activating protein but mammalian Vps39 does not modulate Rab7 GTP binding status. J. Biol. Chem. 285:16814-21.
Siskind LJ, Mullen TD, Romero Rosales K, Clarke CJ, Hernandez-Corbacho MJ, Edinger AL, and LM Obeid (2010). The BCL-2 protein BAK is required for long-chain ceramide generation during apoptosis. J. Biol. Chem. 285:11818-26.
Romero KR, Peralta EP, Guenther GG, Wong SY, and AL Edinger (2009). Rab7 activation by growth factor withdrawal contributes to the induction of apoptosis. Molec. Biol. of the Cell 20:2831-40.
Guenther GG, Peralta EP, Romero KR, Wong SY, Siskind, LJ and AL Edinger (2008). Ceramide starves cells to death by down-regulating nutrient transporter proteins. Proc. Natl. Acad. Sci. 105, 17402–17407.
NIH R01-GM089919 (PI:Edinger). Effects of Sphingolipids on Nutrient Transporter Expression and Bioenergetics. This grant supports studies to identify the molecular mechanism behind sphingolipid-induced nutrient transporter loss.
Department of Defense CDMRP Breast Cancer Research Program BC14027 (PI: Edinger). Using sphingolipids to target metabolism and metastasis in breast cancer.
R21 CA178230 (PI: Edinger, Co-I: Hanessian)NIH-NCI
Identification of the anti-neoplastic target of bioactive FTY720 analogs
Chao Family Comprehensive Cancer Center