Janet V. Cross

Education

  • BS, State University of New York College at Fredonia
  • PhD, Case Western Reserve University

Primary Appointment

  • Assistant Professor, Pathology

Contact

Research Interest(s)

Contribution of the Inflammatory Microenvironment to Tumor Initiation, Progression and Metastasis; Molecular Mechanisms of Cancer Chemoprevention; Anti-Inflammatory Benefits of Dietary Nutrient Compounds

Research Description

The central objective of my lab is to understand how the host immune response is reprogrammed by tumors to promote growth and metastasis. Specifically, we focus on the role of an inflammatory cytokine, the Macrophage Migration Inhibitory Factor (MIF) in cancer. We identified MIF as a target for inhibition by a class of cancer preventive agents present in fresh vegetables, including broccoli. MIF is overexpressed in many cancers, and the degree of overexpression correlates with tumor aggressiveness and metastatic potential. This observation supported our efforts to determine how MIF might contribute to cancer. In recently published work, we have established that MIF promotes tumor growth and is required for tumor metastasis. We demonstrated that MIF carries out its pro-tumor effects through influence over the host immune system, rather than by altering an intrinsic property of the tumor cells. Specifically we discovered that MIF regulates the abundance of a class of immunosuppressive cells within the tumor microenvironment. These cells, monocytic Myeloid Derived Suppressor Cells (Mo-MDSCs) suppress T cell mediated immune responses, thereby protecting the tumor from immune destruction. In this study, we demonstrated that treating tumor bearing mice with our MIF inhibitory compound reduces the abundance of Mo-MDSCs in the tumors, suggesting that we may be able to target MIF therapeutically to inhibit tumor progression through manipulation of the host immune response. The primary goal of ongoing work in our lab is to further understand the mechanisms by which MIF regulates the tumor microenvironment to promote tumor progression. Additionally, we continue to evaluate the potential utility of our inhibitor as a therapeutic approach in other MIF-dependent inflammatory disease processes.

Selected Publications

  • Villarreal-Calderon R, Luévano-González A, Aragón-Flores M, Zhu H, Yuan Y, Xiang Q, Yan B, Stoll K, Cross J, Iczkowski K, Mackinnon A. Antral atrophy, intestinal metaplasia, and preneoplastic markers in Mexican children with Helicobacter pylori-positive and Helicobacter pylori-negative gastritis. Annals of diagnostic pathology. 2014;18(3): 129-35. PMID: 24656654
  • Calderón-Garcidueñas L, Cross J, Franco-Lira M, Aragón-Flores M, Kavanaugh M, Torres-Jardón R, Chao C, Thompson C, Chang J, Zhu H, D'Angiulli A. Brain immune interactions and air pollution: macrophage inhibitory factor (MIF), prion cellular protein (PrP(C)), Interleukin-6 (IL-6), interleukin 1 receptor antagonist (IL-1Ra), and interleukin-2 (IL-2) in cerebrospinal fluid and MIF in serum differentiate urban children exposed to severe vs. low air pollution. Frontiers in neuroscience. 2013;7 183. PMID: 24133408 | PMCID: PMC3794301
  • Calderón-Garcidueñas L, Mora-Tiscareño A, Franco-Lira M, Cross J, Engle R, Aragón-Flores M, Gómez-Garza G, Jewells V, Medina-Cortina H, Solorio E, Chao C, Zhu H, Mukherjee P, Ferreira-Azevedo L, Torres-Jardón R, D'Angiulli A. Flavonol-rich dark cocoa significantly decreases plasma endothelin-1 and improves cognition in urban children. Frontiers in pharmacology. 2013;4 104. PMID: 23986703 | PMCID: PMC3749371
  • Conine S, Cross J. MIF deficiency does not alter glucose homeostasis or adipose tissue inflammatory cell infiltrates during diet-induced obesity. Obesity (Silver Spring, Md.). 2013;22(2): 418-25. PMID: 23804488 | PMCID: PMC3809343
  • Simpson K, Cross J. MIF: metastasis/MDSC-inducing factor? Oncoimmunology. 2013;2(3): e23337. PMID: 23802077 | PMCID: PMC3661162
  • Calderón-Garcidueñas L, Serrano-Sierra A, Torres-Jardón R, Zhu H, Yuan Y, Smith D, Delgado-Chávez R, Cross J, Medina-Cortina H, Kavanaugh M, Guilarte T. The impact of environmental metals in young urbanites' brains. Experimental and toxicologic pathology : official journal of the Gesellschaft für Toxikologische Pathologie. 2012;65(5): 503-11. PMID: 22436577 | PMCID: PMC3383886
  • Simpson K, Templeton D, Cross J. Macrophage migration inhibitory factor promotes tumor growth and metastasis by inducing myeloid-derived suppressor cells in the tumor microenvironment. Journal of immunology (Baltimore, Md. : 1950). 2012;189(12): 5533-40. PMID: 23125418 | PMCID: PMC3518629
  • Victor K, Rady J, Cross J, Templeton D. Proteomic profile of reversible protein oxidation using PROP, purification of reversibly oxidized proteins. PloS one. 2012;7(2): e32527. PMID: 22389707 | PMCID: PMC3289665
  • Zhou J, Joplin D, Cross J, Templeton D. Sulforaphane inhibits prostaglandin E2 synthesis by suppressing microsomal prostaglandin E synthase 1. PloS one. 2012;7(11): e49744. PMID: 23166763 | PMCID: PMC3500324
  • Lyons C, Victor K, Moshnikov S, Bachmann L, Baras A, Dettmann K, Cross J, Templeton D. PICquant: a quantitative platform to measure differential peptide abundance using dual-isotopic labeling with 12C6- and 13C6-phenyl isocyanate. Analytical chemistry. 2011;83(3): 856-65. PMID: 21192683 | PMCID: PMC3079250
  • Gutierrez G, Tsuji T, Cross J, Davis R, Templeton D, Jiang W, Ronai Z. JNK-mediated phosphorylation of Cdc25C regulates cell cycle entry and G(2)/M DNA damage checkpoint. The Journal of biological chemistry. 2010;285(19): 14217-28. PMID: 20220133 | PMCID: PMC2863176
  • Templeton D, Aye M, Rady J, Xu F, Cross J. Purification of reversibly oxidized proteins (PROP) reveals a redox switch controlling p38 MAP kinase activity. PloS one. 2010;5(11): e15012. PMID: 21085594 | PMCID: PMC2981573
  • Bhattacharyya A, Chattopadhyay R, Burnette B, Cross J, Mitra S, Ernst P, Bhakat K, Crowe S. Acetylation of apurinic/apyrimidinic endonuclease-1 regulates Helicobacter pylori-mediated gastric epithelial cell apoptosis. Gastroenterology. 2009;136(7): 2258-69. PMID: 19505426 | PMCID: PMC2694750
  • Cross J, Rady J, Foss F, Lyons C, Macdonald T, Templeton D. Nutrient isothiocyanates covalently modify and inhibit the inflammatory cytokine macrophage migration inhibitory factor (MIF). The Biochemical journal. 2009;423(3): 315-21. PMID: 19723024 | PMCID: PMC2858637
  • Cross J, Foss F, Rady J, Macdonald T, Templeton D. The isothiocyanate class of bioactive nutrients covalently inhibit the MEKK1 protein kinase. BMC cancer. 2007;7 183. PMID: 17894894 | PMCID: PMC2071920
  • Cross J, Templeton D. Regulation of signal transduction through protein cysteine oxidation. Antioxidants & redox signaling. 2006;8(9): 1819-27. PMID: 16987034
  • Zhang C, Kenski D, Paulson J, Bonshtien A, Sessa G, Cross J, Templeton D, Shokat K. A second-site suppressor strategy for chemical genetic analysis of diverse protein kinases. Nature methods. 2005;2(6): 435-41. PMID: 15908922
  • Cross J, Templeton D. Oxidative stress inhibits MEKK1 by site-specific glutathionylation in the ATP-binding domain. The Biochemical journal. 2004;381 675-83. PMID: 15139849 | PMCID: PMC1133876
  • Cross J, Templeton D. Thiol oxidation of cell signaling proteins: Controlling an apoptotic equilibrium. Journal of cellular biochemistry. 2004;93(1): 104-11. PMID: 15352167
  • Zhang D, Lo S, Cross J, Templeton D, Hannink M. Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. Molecular and cellular biology. 2004;24(24): 10941-53. PMID: 15572695 | PMCID: PMC533977
  • Goss V, Cross J, Ma K, Qian Y, Mola P, Templeton D. SAPK/JNK regulates cdc2/cyclin B kinase through phosphorylation and inhibition of cdc25c. Cellular signalling. 2003;15(7): 709-18. PMID: 12742231
  • Seanor K, Cross J, Nguyen S, Yan M, Templeton D. Reactive quinones differentially regulate SAPK/JNK and p38/mHOG stress kinases. Antioxidants & redox signaling. 2003;5(1): 103-13. PMID: 12626122
  • Marozsan A, Torre V, Johnson M, Ball S, Cross J, Templeton D, Quiñones-Mateu M, Offord R, Arts E. Mechanisms involved in stimulation of human immunodeficiency virus type 1 replication by aminooxypentane RANTES. Journal of virology. 2001;75(18): 8624-38. PMID: 11507208 | PMCID: PMC115108
  • Mochida-Nishimura K, Surewicz K, Cross J, Hejal R, Templeton D, Rich E, Toossi Z. Differential activation of MAP kinase signaling pathways and nuclear factor-kappaB in bronchoalveolar cells of smokers and nonsmokers. Molecular medicine (Cambridge, Mass.). 2001;7(3): 177-85. PMID: 11471554 | PMCID: PMC1950026
  • Cross J, Deak J, Rich E, Qian Y, Lewis M, Parrott L, Mochida K, Gustafson D, Vande Pol S, Templeton D. Quinone reductase inhibitors block SAPK/JNK and NFkappaB pathways and potentiate apoptosis. The Journal of biological chemistry. 1999;274(44): 31150-4. PMID: 10531305
  • Deak J, Cross J, Lewis M, Qian Y, Parrott L, Distelhorst C, Templeton D. Fas-induced proteolytic activation and intracellular redistribution of the stress-signaling kinase MEKK1. Proceedings of the National Academy of Sciences of the United States of America. 1998;95(10): 5595-600. PMID: 9576928 | PMCID: PMC20423
  • Fulton S, Cross J, Toossi Z, Boom W. Regulation of interleukin-12 by interleukin-10, transforming growth factor-beta, tumor necrosis factor-alpha, and interferon-gamma in human monocytes infected with Mycobacterium tuberculosis H37Ra. The Journal of infectious diseases. 1998;178(4): 1105-14. PMID: 9806041
  • Paca-Uccaralertkun S, Zhao L, Adya N, Cross J, Cullen B, Boros I, Giam C. In vitro selection of DNA elements highly responsive to the human T-cell lymphotropic virus type I transcriptional activator, Tax. Molecular and cellular biology. 1994;14(1): 456-62. PMID: 8264613 | PMCID: PMC358395