Background
BS, Brigham Young University (1997-2001)
Ph.D., University of Utah (2001-2006)
NIH and American Cancer Society Fellow, Duke University (2006-2011)
Assistant Professor of Medicine, Duke University (2011-2012)
Cancer Research
We integrate molecular/biochemical approaches and mass spectrometry to discover molecular mechanisms that control the growth and survival of cancer cells. A better understanding of these mechanisms gives us the tools to develop more effective and targeted cancer therapies.
A central aim of our lab focuses on the protein 14-3-3, which interacts in a phosphorylation-dependent manner with a vast network of partners. These 14-3-3 interactions regulate essentially all aspects of cancer biology, including cell cycle, anti-apoptotic signaling, Warburg metabolism, immune signaling, and motility/metastasis. In this way, 14-3-3 acts as a cellular hub that orchestrates an entire program of oncogenesis and cancer growth (Figure 1). We have approached 14-3-3 from several angles, including the direct therapeutic targeting of 14-3-3 in cancer and its use as a phospho-probe to identify targetable cancer mechanisms. Currently, we have several projects that have sprung from our work on 14-3-3, many of which have now taken on a life of their own:
1) Mechanisms of autophagy. Cancer cells respond to a variety of stresses by activating a pro-survival recycling process called autophagy (translated literally as ‘self-eating’). Our work in this area started with the discovery of a 14-3-3-mediated molecular switch that controls one of the chief activators of autophagy, ATG9A. Since then, our work has focused on a variety of mysteries about how ATG9A and its interacting partners are regulated to control different steps in the autophagy process.
2) Regulation of oncogenic tyrosine kinases. For a normal cell to become cancerous, it must acquire constitutive growth signaling by activating one or a combination of oncogenic tyrosine kinases. Our work in this area harnesses 14-3-3 as a guide to identify tyrosine kinase mechanisms that promote cancer growth and motility. This work recently led to the identification of a novel cancer therapeutic that is currently under development.
3) Other emerging 14-3-3-mediated mechanisms of cancer growth. An ongoing effort in our lab is to uncover the network of 14-3-3 interactions (the ‘spokes’ off the 14-3-3 hub in figure 1). From such data, we identify important interactions (like those above) and seek to understand 1) how the interaction is regulated and linked to the larger signaling network of the cell; 2) how 14-3-3 binding affects the interacting partner (e.g., inhibition, activation, sequestration); and 3) how the interaction regulates cancer growth. This aspect of our work provides a wellspring of research adventures toward potentially targetable cancer mechanisms.
4) Targeting the hub itself. This project is based on the rationale that targeting 14-3-3 itself, as opposed to specific 14-3-3 interactions, could provide the most robust anti-cancer benefit. Toward this end, we have used our understanding of the molecular basis of 14-3-3 interactions to collaborate in the design of small molecule inhibitors of 14-3-3. In addition, we have used mass spectrometry and bioinformatics to identify post-translational modifications on 14-3-3 that control its interactions with binding partners. This work has revealed how targeting the enzymes that control lysine acetylations within the 14-3-3 binding pocket can inhibit the signaling hub of 14-3-3—effectively shutting down the entire pro-growth program of 14-3-3 with a single hit.
Publications
Hunt JP, Galiardi J, Free TJ, Yang SO, Poole D, Zhao EL, Andersen JL, Wood DW, Bundy BC. (2021) Mechanistic discoveries and stimulation-guided assay optimization of portable hormone biosensors with cell-free protein synthesis. Biotechnology Journal, (epub ahead of print) PMID: 34761537
Pennington KL*, McEwan CM*, Woods J, Muir C, Sahankumari AGP, Eastmond R, Balasooriya ER, Egbert CM, Kaur S, Heaton T, McCormack KK, Piccolo SR, Kurokawa M, Andersen JL. (2021) SGK2, 14-3-3 and HUWE1 cooperate to control the localization, stability and function of the oncoprotein PTOV1. Molecular Cancer Research, (epub ahead of print) PMID: 34654718, *co-first authors
Chan TY*, Egbert CM*, Maxson JE, Siddiqui A, Larsen LJ, Kohler K, Balasooriya ER, Pennington KL, Tsang TM, Frey M, Soderblom EJ, Geng H, Müschen M, Forostyan TV, Free S, Mercenne G, Banks CJ, Valdoz J, Whatcott CJ, Foulks JM, Bearss DJ, O'Hare T, Huang DCS, Christensen KA, Moody J, Warner SL, Tyner JW, Andersen JL. (2021) TNK1 is a ubiquitin-binding and 14-3-3-regulated kinase that can be targeted to block tumor growth. Nature Communications, Sept 9;12(1):5337, PMID: 34504101, *co-first authors
Kananngara A*, Poole D*, McEwan CM, Youngs JC, Weersekara VJ, Thornock AM, Lazaro MT, Balasooriya ER, Oh LM, Soderblom EJ, Lee JJ, Simmons DL, Andersen JL. (2021) BioID reveals an ATG9A interaction with ATG13-ATG101 in the degradation of p62/SQSTM1-ubiquitin clusters. EMBO Reports, (cover story), Oct 5;22(10):e51136, PMID: 34369648, *co-first authors
Yan D, Franzini A, Pomicter AD, Halverson BJ, Antelope O, Mason CC, Ahmann JM, Senina AV, Vellore NA, Jones CL, Zabriskie MS, Than H, Xiao MJ, Scoyk AV, Patel AB, Clair PM, Heaton WL, Owen SC, Andersen JL, Egbert CM, Reisz JA, AD’Alessandro A, Cox JA, Gantz KC, Redwine HM, Iyer SM, Khorashad JS, Rajabi N, Olsen CA, O’Hare T, Deininger MW. (2021) A critical role for SIRT5 in acute myeloid leukemia metabolism. Blood Cancer Discovery, May;2(3):266-287, PMID: 34027418
Banks CJ and Andersen JL. (2019) Post-translational regulation of SOD1. Redox Biology. Sep;26:101270
Chandrasekharan B, Montllor-Albalate C, Colin AE, Andersen JL, Jang YC, Reddi AR. (2019) Cu/Zn Superoide Distmutase-1 regulates the canonical Wnt signaling pathway. Biochemical and Biophysical Research Communications. Jan 1;534:720-726
Hashemi MM, Holden BS, Coburn J, Taylor MF, Weber S, Hilton B, Zaugg AL, McEwan C, Carson R, Andersen JL, Price JC, Deng S, Savage PB. (2019) Proteomic analysis of resistance of gram-negative bacteria to chlorohexidine and impacs on susceptibility to colistin, anti-microbial peptides and ceragenins. Frontiers in Microbiology. Feb 18;10:210
Montllor-Albalate C, Colin AE, Chandrasekharan B, Bolaji N, Andersen JL, Outten FW, Reddi AR. (2019) Extra-mitochondrial Cu/Zn superoxide dismutase (Sod1) is dispensable for protection against oxidative stress but mediates peroxide signaling in Sacchromyces cerevisiae. Redox Biology. Feb;21:101064
Speirs MMP, Swensen AC, Chan TY, Jones PM*, Holman JC*, Harris MB, Maschek JA, Cox JE, Carson RH, Hill J, Andersen JL, Prince, JT, Price JC. (2019) Imbalanced sphingolipid signaling is maintained as a core proponent of a cancerous phenotype in spite of metabolic pressure and epigenetic drift. Oncotarget. 11;10(4) 449-479
Telles Freitas CM, Burrell HR, Valdoz JC, Hamblin GJ, Raymond CM, Cox TD, Johnson DK, Andersen JL, Weber KS, Bridgewater LC. (2019) The nuclear variant of bone morphogenetic protein 2 (nBMP2) is expressed in macrophages and alters calcium response. Scientific Reports Jan 30;9(1):934
Pennington KL, Chan TY, Torres MP, Andersen JL. (2018) The dynamic and stress-adaptive hub of 14-3-3: Emerging mechanisms of regulation and context-dependent protein-protein interactions. Oncogene. 37:5587-5604
Banks C, Rodriguez N, Gashler KR, Pandya RR, Whited MD, Soderblom, EJ, Thompson JW, Moseley mA, Reddi AR, Tessem JS, Torres MP, Bikman BT, Andersen JL. (2017) Acylation of Superoxide Dismutase (SOD1) at K122 governs SOD1-mediated inhibition of mitochondrial respiration. Molecular and Cellular Biology. 26:37(20)
Mortenson JB, Heppler LN, Banks CJ, Whited M, Weerasekara VK, Piccolo SR, Johnson WE, Thompson JW, Andersen JL. (2015) HDAC6 modulates the pro-survival activity of 14-3-3z via deacetylation of lysines within the 14-3-3z binding pocket. Journal of Biological Chemistry. 15;290(20):12487-96
Weerasekara VK, Panek DJ, Broadbent DG, Mortenson JB, Mathis AD, Logan GN, Prince JT, Thomson DM, Thompson JW, Andersen JL. (2014) Metabolic stress-induced rearrangement of the 14-3-3z interactome promotes autophagy via a ULK1- and AMPK-regulated 14-3-3z interaction with phosphorylated Atg9A. Molecular and Cellular Biology (cover story). 34(24):4379-88
Johnson SE, Lindblom KR, Robeson A, Stevens RD, Ilkayeva OR, Newgard CB, Kornbluth S, Andersen JL. (2013) Metabolomics profiling reveals a role for caspase-2 in lipoapoptosis. Journal of Biological Chemistry 17;288(20):14463-75
Thompson, JW, Robeson A, Andersen JL. (2013) Biotin-switch methods to identify Sirtuin substrates. Methods Enzymology 1077:133-48
Andersen JL, Kornbluth S. (2013) The tangled circuitry of metabolism and apoptosis. Molecular Cell 2;43(5): 832-84
Andersen JL, Kornbluth S. (2012) Mcl-1 rescues a glitch in the matrix. Nature Cell Biology 30;14(6): 563-565
Parrish AB, Kim J, Kurokawa M, Matsuura K, Freel CD, Andersen JL, Johnson CE, Kornbluth S. (2012) RSK mediated phosphorylation and 14-3-3e binding of Apaf-1 suppresses cytochrome c-induced apoptosis. EMBO J. 31(5): 1279-1292
Andersen JL, Thompson JW, Lindblom KR, Johnson ES, Yang CS, Lilley LR, Freel CD, Mosely MA, Kornbluth S. (2011) A biotin switch-based proteomics approach identifies 14-3-3z as a target of sirt1 in the metabolic regulation of caspase-2. Molecular Cell 43(5): 834-842 (cover story)
Andersen JL, and Kornbluth S. (2011) Meeting the N-terminal end with acetylation. Cell 146(4): 503-505
Andersen JL, Johnson CE, Freel CD, Parrish AB, Day JL, Buchakjian MR, Nutt LK, Thompson JW, Moseley MA, Kornbluth S. (2009) Restraint of apoptosis during mitosis through interdomain phosphorylation of caspase-2. EMBO J. 28(20): 3216-3227
Andersen JL, Kornbluth S. (2009) A cut above the other caspases. Molecular Cell 25;35(6): 733-734
Nutt LK, Buchakjian MR, Gan E, Darbandi R, Sook-Young Y, Wu JQ, Miyamoto J, Gibbon JA, Andersen JL, Freel CD, Tang W, He C, Kurokawa M, Wang Y Margolis SS, Fissore RA, Kornbluth S. (2009) Metabolic control of oocyte apoptosis mediated by 14-3-3zeta-regulated dephosphorylation of caspase-2. Developmental Cell 16(6): 856-866
Andersen JL, Le Rouzic E, Planelles V. (2008) HIV-1 Vpr: Mechanisms of G2 arrest and apoptosis. Experimental and Molecular Pathology 85(1): 2-10
Andersen JL, DeHart JL, Zimmerman ES, Ardon O, Kim B, Jacquot G, Benichou S, Planelles V. (2007) HIV-1 Vpr-induced apoptosis is cell cycle-dependent and requires Bax but not ANT. PLoS Pathogens 2(12): e127
Ardon O, Zimmerman ES, Andersen JL, Dehart JL, Blackett J, Planelles V. (2006) Induction of G2 arrest and binding to cyclophilin A are independent phenotypes of Human Immunodeficiency Virus type 1 Vpr. Journal of Virology 80(8): 3694-3700
Dehart JL, Andersen JL, Zimmerman E, Ardon O, An DS, Blackett J, Planelles V. (2005) ATR is dispensable for retroviral integration. Journal of Virology 79(3): 1389-1396
Andersen JL, Zimmerman ES, Dehart JL, Murala S, Ardon O, Blackett J, Chen J, Planelles V. (2005) ATR and Gadd45 alpha mediate HIV-1 Vpr-induced apoptosis. Cell Death and Differentiation 12(4): 326-334
Andersen JL, Planelles V. (2005) The role of Vpr in HIV-1 pathogenesis. Current HIV Research 3(1): 43-51
Zimmerman ES, Chen J, Andersen JL, Ardon O, Dehart JL, Blackett J, Murala S, Neghiem P, Planelles V. (2004) HIV-1 Vpr-mediated G2 arrest requires Rad17 and Hus1 and induces nuclear accumulation of BRCA1 and gamma-H2AX foci. Molecular and Cellular Biology 24(21): 9286-9294