Janet V. Cross

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Primary Appointment

Associate Professor, Pathology

Education

  • BS, Recombinant Gene Technology, Medical Technology, State University of New York College at Fredonia
  • PhD, Molecular Biology and Microbiology, Case Western Reserve University

Research Interests

Contribution of the Inflammatory Microenvironment to Tumor Initiation, Progression and Metastasis; Molecular Mechanisms of Cancer Chemoprevention

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.

Personal Statement

The central objective of my lab is to understand how the host immune response is reprogrammed by tumors to promote growth and metastasis. My entire career has focused on the study of mechanisms that contribute to tumor development. Early on, my work centered on the regulation of cell signaling pathways and the aberrations in these networks that promote cell growth, prevent cell death or otherwise contribute to cancer. In the course of these studies, I performed an unbiased proteomics screen to identify molecular targets that might explain the anti-cancer activities of a well-studied class of cancer preventive compounds. We expected to identify a kinase or a transcription factor that might mediate their protective properties by interfering with signaling responses within the tumor cell. Instead, we identified an inflammatory cytokine, the Macrophage Migration Inhibitory Factor (MIF), as the major target of these cancer agents, a discovery that has taken my lab in an exciting new direction.

Training

  • Biodefense & Infectious Diseases Short-Term Training to Increase Diversity in Biomedical Sciences

Selected Publications

2019

Gigliotti, J. C., Tin, A., Pourafshar, S., Cechova, S., Wang, Y. T., Sung, S. -S. J., . . . Le, T. H. (2020). GSTM1 Deletion Exaggerates Kidney Injury in Experimental Mouse Models and Confers the Protective Effect of Cruciferous Vegetables in Mice and Humans. JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 31(1), 102-116. doi:10.1681/ASN.2019050449

Calderon-Garciduenas, L., Gonzalez-Maciel, A., Mukherjee, P. S., Reynoso-Robles, R., Perez-Guille, B., Gayosso-Chavez, C., . . . Maher, B. A. (2019). Combustion- and friction-derived magnetic air pollution nanoparticles in human hearts. ENVIRONMENTAL RESEARCH, 176. doi:10.1016/j.envres.2019.108567

2018

Balogh, K. N., Templeton, D. J., & Cross, J. V. (2018). Macrophage Migration Inhibitory Factor protects cancer cells from immunogenic cell death and impairs anti-tumor immune responses. PLOS ONE, 13(6). doi:10.1371/journal.pone.0197702

2017

Dill, E. A., Gru, A. A., Atkins, K. A., Friedman, L. A., Moore, M. E., Bullock, T. N., . . . Mills, A. M. (2017). PD-L1 Expression and Intratumoral Heterogeneity Across Breast Cancer Subtypes and Stages An Assessment of 245 Primary and 40 Metastatic Tumors. AMERICAN JOURNAL OF SURGICAL PATHOLOGY, 41(3), 334-342. doi:10.1097/PAS.0000000000000780

Gottlieb, C. E., Mills, A. M., Cross, J. V., & Ring, K. L. (2017). Tumor-associated macrophage expression of PD-L1 in implants of high grade serous ovarian carcinoma: A comparison of matched primary and metastatic tumors. GYNECOLOGIC ONCOLOGY, 144(3), 607-612. doi:10.1016/j.ygyno.2016.12.021

Balogh, K. N., & Cross, J. V. (2017). A role for Macrophage Migration Inhibitory Factor (MIF) in breast cancer growth and metastasis. CANCER IMMUNOLOGY RESEARCH, 5(3). doi:10.1158/2326-6074.TUMIMM16-A03

2016

Damle, S. R., Martin, R. K., Cross, J. V., & Conrad, D. H. (2017). Macrophage migration inhibitory factor deficiency enhances immune response to Nippostrongylus brasiliensis. MUCOSAL IMMUNOLOGY, 10(1), 205-214. doi:10.1038/mi.2016.29

2014

Villarreal-Calderon, R., Luevano-Gonzalez, A., Aragon-Flores, M., Zhu, H., Yuan, Y., Xiang, Q., . . . Mackinnon, A. C. J. (2014). Antral atrophy, intestinal metaplasia, and preneoplastic markers in Mexican children with Helicobacter pylori-positive and Helicobacter pylori-negative gastritis. ANNALS OF DIAGNOSTIC PATHOLOGY, 18(3), 129-135. doi:10.1016/j.anndiagpath.2014.02.003

2013

Conine, S. J., & Cross, J. V. (2014). MIF Deficiency Does Not Alter Glucose Homeostasis or Adipose Tissue Inflammatory Cell Infiltrates during Diet-Induced Obesity. OBESITY, 22(2), 418-425. doi:10.1002/oby.20555

Simpson, K. D., & Cross, J. V. (2013). MIF Metastasis/MDSC-inducing factor?. ONCOIMMUNOLOGY, 2(3). doi:10.4161/onci.23337

Calderon-Garciduenas, L., Mora-Tiscareno, A., Franco-Lira, M., Cross, J. V., Engle, R., Aragon-Flores, M., . . . D'Angiulli, A. (2013). Flavonol-rich dark cocoa significantly decreases plasma endothelin-1 and improves cognition in urban children. FRONTIERS IN PHARMACOLOGY, 4. doi:10.3389/fphar.2013.00104

Calderon-Garciduenas, L., Cross, J. V., Franco-Lira, M., Aragon-Flores, M., Kavanaugh, M., Torres-Jardon, R., . . . D'Angiulli, A. (2013). Brain immune interactions and air pollution: macrophage inhibitory factor (MIF), prion cellular protein (PrPc), 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, 7. doi:10.3389/fnins.2013.00183

2012

Simpson, K. D., Templeton, D. J., & Cross, J. V. (2012). Macrophage Migration Inhibitory Factor Promotes Tumor Growth and Metastasis by Inducing Myeloid-Derived Suppressor Cells in the Tumor Microenvironment. JOURNAL OF IMMUNOLOGY, 189(12), 5533-5540. doi:10.4049/jimmunol.1201161

Calderon-Garciduenas, L., Serrano-Sierra, A., Torres-Jardon, R., Zhu, H., Yuan, Y., Smith, D., . . . Guilarte, T. R. (2013). The impact of environmental metals in young urbanites' brains. EXPERIMENTAL AND TOXICOLOGIC PATHOLOGY, 65(5), 503-511. doi:10.1016/j.etp.2012.02.006

Zhou, J., Joplin, D. G., Cross, J. V., & Templeton, D. J. (2012). Sulforaphane Inhibits Prostaglandin E2 Synthesis by Suppressing Microsomal Prostaglandin E Synthase 1. PLOS ONE, 7(11). doi:10.1371/journal.pone.0049744

Victor, K. G., Rady, J. M., Cross, J. V., & Templeton, D. J. (2012). Proteomic Profile of Reversible Protein Oxidation Using PROP, Purification of Reversibly Oxidized Proteins. PLOS ONE, 7(2). doi:10.1371/journal.pone.0032527

2010

Lyons, C. E., Victor, K. G., Moshnikov, S. A., Bachmann, L. M., Baras, A. S., Dettmann, K. M., . . . Templeton, D. J. (2011). PICquanit: A Quantitative Platform To Measure Differential Peptide Abundance Using Dual-Isotopic Labeling with 12C6- and 13C6-Phenyl Isocyanate. ANALYTICAL CHEMISTRY, 83(3), 856-865. doi:10.1021/ac102461e

Templeton, D. J., Aye, M. -S., Rady, J., Xu, F., & Cross, J. V. (2010). Purification of Reversibly Oxidized Proteins (PROP) Reveals a Redox Switch Controlling p38 MAP Kinase Activity. PLOS ONE, 5(11). doi:10.1371/journal.pone.0015012

Gutierrez, G. J., Tsuji, T., Cross, J. V., Davis, R. J., Templeton, D. J., Jiang, W., & Ronai, Z. A. (2010). JNK-mediated Phosphorylation of Cdc25C Regulates Cell Cycle Entry and G2/M DNA Damage Checkpoint. JOURNAL OF BIOLOGICAL CHEMISTRY, 285(19), 14217-14228. doi:10.1074/jbc.M110.121848