Melanie Simpson

Research Interests:

Mechanisms of Prostate Cancer Progression

Enzymes of Hyaluronan Metabolism

In Vivo Imaging

Research Overview

Prostate cancer is the most commonly diagnosed cancer in American men and the second leading cause of male cancer death. Our lab is studying molecular mechanisms that contribute to advanced prostate cancer, which is very difficult to treat. We have several ongoing projects that use a combination of biochemical and cell culture techniques, as well as mouse models of tumor growth and metastasis. Our goal is to address specific mechanistic questions about aggressive growth and spread of prostate cancer.

Normal cell proliferation within the prostate is dependent on androgen hormones, which are provided by the testes and converted to a more potent form within prostate epithelial cells. Most prostate cancer is thought to originate among the luminal epithelial cells when genetic or physical insults induce changes to the cells and/or their microenvironment that permit inappropriate proliferation. Progression occurs when tumor cells become able to manipulate their local environment by remodeling the extracellular space. Cancerous cells may invade the lymphatic system and/or the bloodstream, and colonize other tissues. Localized prostate cancer has a number of treatment options and high treatment success, but there are many questions that need to be answered to combat advanced cancer. Several key issues our research seeks to address include tissue remodeling by the tumor cells, hormone elimination versus sequestration in tumor cells, and molecular changes that influence metastatic potential.

Lab Members

Christine Booth

Graduate Student
B.S. 2005 University of Pretoria, South Africa

M.Eng. 2012  Chemical and Biomolecular Engineering, University of Nebraska

Research Project:
Role of hyaluronan based signals in stromal-epithilial crosstalk and progression of prostate cancer

E-mail Christine

George Grady

Graduate Student (co-advised w/Dr. Joe Barycki)
 B.S. 2013 Biochemistry, Marietta University

Research Project:
Allosteric control of UDP-glucose Dehydrogenase

E-mail George

Eryn Lee

Graduate Student
 B.S. 2014 Biochemistry, St. Edward's University

Research Project:
Human hyaluronidases and their involvement in prostate cancer progression

E-mail Eryn

Linlin (Lily) Ma

Research Technician
 B.A. 2014 Chengde Medical University

Research Project:
Functional role of UGDH in castration resistant prostate cancer

E-mail Lily

Caitlin McAtee

Post-doctoral Researcher
B.S. 2008  Gettysburg College

Ph.D. 2014 Biochemistry,  University of Nebraska

Research Project:
Impact of the hyaluronidase Hyal1 on prostate cancer progression through accelerated vesicle trafficking and cell-cell communication

E-mail Caitlin

Michelle Palmer

Graduate Student (co-advised w/Dr. Joe Barycki)
Started 2013

Research Project:
Probing metabolite partitioning to identify rate limiting factors in alternative pathway use

E-mail Michelle

Allison Vlach

Undergraduate Researcher
Started January, 2014

Research Project:
Biochemical characterization of human hyaluronidases

E-mail Allison

Brenna Zimmer

Graduate Student
B.S. 2009 Biochemistry and Molecular Biology, Emporia State University
M.S. 2011 Physical Science, Emphasis in Chemistry, Emporia State University

Research Project:
Testing the role of UDP-glucose dehydrogenase in prostate tumor androgen sensitivity

E-mail Brenna

Publications:

Brenna M. Zimmer, Michelle E. Howell, Qin Wei, Linlin Ma, Trevor Romsdahl, Eileen G. Loughman, Jonathan E. Markham, Javier Seravalli, Joseph J. Barycki, and Melanie A. Simpson. 2016. Loss of exogenous androgen dependence by prostate tumor cells is associated with elevated glucuronidation potential. Hormones and Cancer. 2016 Jun 15. [Epub ahead of print] PMID: 27307252

George Grady, Ashley Thelen, Jaleen Albers, Ju T, Jiantao Guo, Joseph J. Barycki+, Melanie A. Simpson+. 2016. Inhibiting hexamer disassembly of human UDP-glucose dehydrogenase by photoactivated amino acid cross-linking. Biochemistry. Jun 7, 2016. 55(22), 3157-64. PMID: 27198584. +co-corresponding authors

McAtee CO, Berkebile AR, Elowsky C, Fangman T, Barycki JJ, Wahl JK 3rd, Khalimonchuk O, Naslavsky N, Caplan S, Simpson MA. (2015) Hyaluronidase Hyal1 increases tumor cell proliferation and motility through accelerated vesicle trafficking. J Biol Chem. 2015 Apr 8. pii: jbc.M115.647446. [Epub ahead of print] PMID: 25855794

Haney SL, Hlady RA, Opavska J, Klinkebiel D, Pirruccello SJ, Dutta S, Datta K, Simpson MA, Wu L, Opavsky R.
(2015) Methylation-independent repression of Dnmt3b contributes to oncogenic activity of Dnmt3a in mouse MYC-induced T-cell lymphomagenesis. Oncogene 2015 Feb 2  doi: 10.1038/onc.2014.472. [Epub ahead of print]
PMID: 25639876

McAtee CO, Barycki JJ and Simpson MA. (2014) Emerging roles for hyaluronidase in cancer metastasis and therapy. Invited review. Adv Cancer Res. 2014;123:1-34. doi: 10.1016/B978-0-12-800092-2.00001-0.

Liu Y, Hyde AS, Simpson MA, Barycki JJ. (2014) Emerging regulatory paradigms in glutathione metabolism. Invited review. Adv Cancer Res. 2014;122C:69-101. doi: 10.1016/B978-0-12-420117-0.00002-5.

Kovar JL, Cheung LL, Simpson MA, Olive DM. (2014) Pharmacokinetic and biodistribution assessment of a near infrared-labeled PSMA-specific small molecule in tumor-bearing mice. Prostate Cancer. 2014:104248. doi: 10.1155/2014/104248.

Peters SL, Hlady R, Opavska J, Klinkebiel D, Perruccello SJ, Talmon GA, Sharp JG, Wu L, Jaenisch R, Simpson MA, Karpf AR and Opavsky R. (2014) Tumor suppressor functions of Dnmt3a and Dnmt3b in the prevention of malignant lymphopoiesis. Leukemia. 28(5): 1138-42.

Hyde AS*, Thelen AM*, Barycki JJ, Simpson MA. (2013) UDP-glucose dehydrogenase activity and optimal downstream cellular function require dynamic reorganization at the dimer-dimer subunit interfaces. J Biol Chem 288(49): 35049-35057. *Co-first authors

Peters SL, Hlady R, Opavska J, Klinkebiel D, Novakova S, Smith LM, Lewis RE, Karpf AR, Simpson MA, Wu L and Opavsky R. (2013) An essential role for Dnmt1 in prevention and maintenance of MYC-induced T cell lymphomas. Mol Cell Biol. 33(21): 4321-4333.

Kovar JL, Curtis E, Othman S, Simpson MA and Olive DM. (2013) Characterization of IRDye 800CW chlorotoxin as a targeting agent for brain tumors. Anal Biochem. 440(2): 212-9.

Stephens E, Saltarrelli J, Balaoing LR, Baggett S, Nandi I, Anderson K, Morrisett J, Reardon M, Simpson M, Weigel P, Olmsted-Davis E, Davis A and Grande-Allen KJ. (2012) Hyaluronan turnover and hypoxic brown adipocytic differentiation are co-localized with ossification in calcified human aortic valves. Pathol Res Pract. 208(11): 642-50.

Hyde AS, Farmer EL, Easley KE, van Lammeren K, Christoffels VM, Barycki JJ, Bakkers J, and Simpson MA. (2012) UDP-glucose dehydrogenase polymorphisms from patients with congenital heart valve defects disrupt enzyme stability and quaternary assembly. J Biol Chem 287(39): 32708-16.

Natarajan SK, Zhu W, Zhang L, Liang X, Demers AJ, Zimmerman M, Simpson MA and Becker DF. (2012) Proline dehydrogenase is essential for proline protection against hydrogen peroxide induced cell death. Free Radicals in Biology and Medicine. 53(5): 1181-91.

Simpson MA*, Weigel JA and Weigel PH. (2012) Systemic blockade of the hyaluronan receptor for endocytosis (HARE) prevents lymph node metastasis of prostate cancer. Int J Cancer. 131: E836–E840.  *Corresponding author

Hlady RA, Novakova S, Opavska J, Klinkebiel D, Peters SL, Bies J, Hannah J, Iqbal J, Anderson KM, Siebler HM, Smith LM, Greiner TC, Bastola D, Joshi S, Lockridge O, Simpson MA, Felsher DW, Wagner KU, Chan WC, Christman JK, Opavsky R. (2012) Loss of Dnmt3b function upregulates the tumor modifier Ment and accelerates mouse lymphomagenesis. J Clin Invest. 2012 Jan 3;122(1):163-77. doi: 10.1172/JCI57292. Epub 2011 Dec 1.

Willis MN, Liu Y, Biterova EI, Simpson MA, Kim H, Lee J, Barycki JJ. (2011) Enzymatic Defects Underlying Hereditary Glutamate Cysteine Ligase Deficiency Are Mitigated by Association of the Catalytic and Regulatory Subunits.  Biochemistry.  Jul 26;50(29):6508-17. Epub 2011 Jun 29.

Kovar JL, Xu X, Draney D, Cupp A, Simpson MA, Michael Olive D. (2011) Near-infrared-labeled tetracycline derivative is an effective marker of bone deposition in mice.  Anal Biochem. Sep 15;416(2):167-73. Epub 2011 May 12.

Bharadwaj AG, Goodrich NP, McAtee CO, Haferbier K, Oakley GG, Wahl III JK, and Simpson MA. (2011) Hyaluronan suppresses prostate tumor cell proliferation through diminished expression of N-cadherin and aberrant growth factor receptor signaling. Exp Cell Res. 317(8): 1214-1225.

Huang D, Casale G, Tian J, Lele SM, Pisarev VM, Simpson MA and Hemstreet III GP. (2010) UDP-glucose dehydrogenase as a novel field-specific candidate biomarker of prostate cancer. Int J Cancer 126(2): 315-327.

Simpson MA. Hyaluronan synthesis and turnover in prostate cancer. (2009) Chapter 16 in Hyaluronan in Cancer Biology, pp. 309-327. Ed. Robert Stern, Oxford: Academic Press.

Zhang L, Bharadwaj AG, Casper A, Barkley J, Barycki JJ and Simpson MA. (2009) Hyaluronidase activity of human Hyal1 requires active site acidic and tyrosine residues. J Biol Chem 284: 9433-9442.

Wei Q, Galbenus R, Raza A, Cerny RL and Simpson MA. (2009) Androgen-stimulated UDP-glucose dehydrogenase expression limits prostate androgen availability without impacting hyaluronan levels. Cancer Research 69(6): 2332-2339.

Bharadwaj AG, Kovar JL, Loughman E, Elowsky C, Oakley GG and Simpson MA. (2009) Spontaneous metastasis of prostate cancer is promoted by excess hyaluronan synthesis and processing. Amer J Pathol. 174(3): 1027-1036.

Kovar JL, Ke S, Volcheck WM, Sevick-Muraca E, Simpson MA and Olive DM. (2009) Characterization and performance of a near infrared 2-deoxyglucose optical imaging agent for mouse cancer models. Anal Biochem, 384(2):254-62.

Simpson MA and Lokeshwar VB. (2008) Hyaluronan and hyaluronidase in genitourinary tumors. Invited Review. Frontiers in Bioscience 13: 5664-80.

Bharadwaj AG, Rector K, Simpson MA. (2007) Inducible hyaluronan production reveals differential effects on prostate tumor cell growth and tumor angiogenesis. J Biol Chem. 282(28): 20561-72.

Kovar JL, Simpson MA, Geschwender A and Olive DM. (2007) A systematic approach to the development of fluorescent contrast agents for optical imaging of mouse cancer models. Review. Anal Biochem. 367(1): 1-12.

Kovar JL, Volcheck WM, Chen J and Simpson MA. (2007) Purification method directly influences effectiveness of an epidermal growth factor-coupled targeting agent for noninvasive tumor detection in mice. Anal Biochem. 361(1): 47-54.

Easley KE, Sommer BJ, Boanca G, Barycki JJ, and Simpson MA. (2007) Characterization of human UDP-glucose dehydrogenase reveals critical catalytic roles for lysine 220 and aspartate 280. Biochemistry 46(2): 369-78.

Kovar JL, Johnson MA, Volcheck WM, Chen J and Simpson MA. (2006) Hyaluronidase induces prostate tumor metastasis in an orthotopic mouse model. Amer J Pathol. 169(4): 1415-26.

Simpson MA. (2006) Concurrent expression of hyaluronan biosynthesis and processing enzymes promotes growth and vascularization of prostate tumors in mice. Amer J Pathol. 169(1): 247-57.

McCarthy J, Turley E, Wilson C, Price M, Bullard K, Beck M, Simpson M. (2005) Hyaluronan biosynthesis in prostate carcinoma growth and metastasis. In Hyaluronan: Structure, Metabolism, Biological activities, Therapeutic Applications; Chapter 4, Hyaluronan and Tumors. Eds E.A. Balasz and V.C. Hascall.

Sommer BJ, Barycki JJ, and Simpson MA. (2004) Characterization of human UDP-glucose dehydrogenase: Cys 276 is required for the second of two successive oxidations. J Biol Chem. 279: 23590-96.

Yang J, Price MA, Wilson C, Ferrone S, Neudauer CL, Xia H, Iida J, Simpson MA, McCarthy JB. (2004) Melanoma chondroitin sulfate proteoglycan enhances focal adhesion kinase and ERK activation by distinct mechanisms. J Cell Biol. 165: 881-91.

Kim HR, Wheeler MA, Wilson CM, Iida J, Eng D, Simpson MA, McCarthy JB and Bullard KM. (2004) Hyaluronan Facilitates Invasion of Colon Carcinoma Cells In Vitro via Interaction with CD44. Cancer Res. 64: 4569-76.

McCarthy JB and Simpson MA. (2003) Hyaluronan in prostate cancer progression. Glycoforum online reviews (invited).

Bullard KM, Kim HR, Wheeler MA, Wilson CM, Neudauer CL, Simpson MA, McCarthy JB. (2003) Hyaluronan synthase-3 is upregulated in metastatic colon carcinoma cells and manipulation of expression alters matrix retention and cellular growth. Int J Cancer 107(5): 739-46.

Simpson MA, Wilson CM, McCarthy JB. (2002) Inhibition of prostate tumor cell hyaluronan synthesis impairs subcutaneous growth and vascularization in immunocompromised mice. Amer J Pathol, 161(3): 849-857.

Simpson MA, Wilson CM, Furcht LT, Spicer AP, Oegema TR, McCarthy JB. (2002) Manipulation of hyaluronan synthase expression in prostate adenocarcinoma cells alters pericellular matrix retention and adhesion to bone marrow endothelial cells. J Biol Chem. 277: 10050-10057.

Simpson MA, Reiland J, Burger SR, Furcht LT, Spicer AP, Oegema TR Jr, McCarthy JB. (2001) Hyaluronan Synthase Elevation in Metastatic Prostate Carcinoma Cells Correlates with Hyaluronan Surface Retention, a Prerequisite for Rapid Adhesion to Bone Marrow Endothelial Cells. J Biol Chem. 276(21): 17949-17957.

Iida J, Pei D, Kang T, Simpson MA, Herlyn M, Furcht LT, McCarthy JB. (2001) Melanoma Chondroitin Sulfate Proteoglycan Regulates Matrix Metalloproteinase-dependent Human Melanoma Invasion into Type I Collagen. J Biol Chem. 276(22): 18786-18794.

Eisenmann KM, McCarthy JB, Simpson MA, Keely PJ, Guan JL, Tachibana K, Lim L, Manser E, Furcht LT, Iida J. (1999) Melanoma Chondroitin Sulphate Proteoglycan Regulates Cell Spreading Through Cdc42, Ack-1 and p130cas. Nature Cell Biol. 1: 507-513.

Simpson MA, LiCata V, Ribarik Coe N, Bernlohr DA. (1999) Biochemical and Biophysical Analysis of the Intracellular Lipid-binding Proteins of Adipocytes. Mol Cell Biochem. 192: 33-40.

Coe NR, Simpson MA, Bernlohr DA. (1999) Targeted Disruption of the Adipocyte Lipid Binding Protein (aP2 protein) Gene Impairs Fat Cell Lipolysis and Increases Cellular Fatty Acid Levels. J Lipid Res. 40: 967-72.

Simpson MA and Bernlohr DA. (1998) Testing of the Portal Hypothesis: Analysis of a Series of Adipocyte Lipid Binding Protein Phenylalanine 57 Mutants. Biochemistry 37: 10980-10986.

Bernlohr DA, Ribarik Coe N, Simpson MA, Hertzel AV. (1997) Regulation of gene expression in adipose cells by polyunsaturated fatty acids. Adv Exp Med Biol. 422: 145-156.

Ory J, Kane CD, Simpson MA, Banaszak LJ and Bernlohr DA. (1997) Biochemical and Crystallographic Analyses of a Portal Mutant of the Adipocyte Lipid-binding Protein. J Biol Chem. 272: 9793-9801.

Bernlohr DA, Simpson MA, Hertzel AV and Banaszak LJ. (1997) Intracellular Lipid-binding Proteins and their Genes. Ann Rev Nutr. 17: 277-303.

Bernlohr DA and Simpson MA. (1996) Adipose tissue and lipid metabolism. In Biochemistry of Lipids, Lipoproteins and Membranes. D.E. Vance and J.E. Vance (Eds.). Elsevier Science BV.

LaLonde JM, Levenson (Simpson) MA, Roe JJ, Bernlohr DA and Banaszak LJ. (1994) Adipocyte Lipid-binding Protein Complexed with Arachidonic Acid: Titration Calorimetry and X-ray Crystallographic Studies. J Biol Chem. 269: 25339-25347.

News and Links

Lab Safety Manual

June 1, 2015 - Congratulations to Jeremy on his Benjamin M. Sahagian Scholarship Award (2015-2016) and Danielle on her UCARE Award (Summer 2015).

May 5, 2015 - Allison Vlach has been selected as a University of Nebraska Beckman's Scholar.  This prestigious  award is granted by the Arnold and Mabel Beckman Foundation and provides scholarship funds to each student to conduct research under the direction of a UNL faculty mentor.  Congratulations Allison!

April 16, 2015 - Jeremy Payne has received UNL's 2015 Outstanding Student Leadership Award.  The Outstanding Student Leadership Award is one of the highest awards presented to students, recognizing outstanding leadership in academic, co-curricular, and/or extracurricular activities and involvement.  Congratulations Jeremy!

April 10, 2015 - Congratulations to Caitlin McAtee and Abbey Berkebile on their publication in the Journal of Biological Chemistry. 

McAtee CO, Berkebile AR, Elowsky C, Fangman T, Barycki JJ, Wahl JK 3rd, Khalimonchuk O, Naslavsky N, Caplan S, Simpson MA. (2015) Hyaluronidase Hyal1 increases tumor cell proliferation and motility through accelerated vesicle trafficking. J Biol Chem. 2015 Apr 8. pii: jbc.M115.647446. [Epub ahead of print] PMID: 25855794

July 29, 2014 - Congratulations to Caitlin McAtee on the publication of her review on human hyaluronidases! The manuscript was published today in Advances in Cancer Research:

McAtee CO, Barycki JJ and Simpson MA. (2014) Emerging roles for hyaluronidase in cancer metastasis and therapy. Invited review. Adv Cancer Res. 2014;123:1-34. doi:10.1016/B978-0-12-800092-2.00001-0.

May 9, 2014 - Congratulations to Dr. Aja Hyde and Dr. Caitlin McAtee on the completion of their Ph.D. programs!