Anand Mehta, DPhil
SmartState Endowed Chair of Proteomic Biomarkers
1999 D.Phil, University of Oxford, Biochemistry
1991 B.A University of Delaware, Biology
Office: CRI 310
2013-2016 Professor (with tenure), Department of Microbiology and Immunology, Drexel University College of Medicine
2004-2014 Associate Director for the Drexel Institute for Biotechnology and Virology Research, Doylestown, PA.
2004-2013 Associate Professor, Department of Microbiology and Immunology, Drexel University College of Medicine
1999-2004 Research Assistant Professor, Department of Biochemistry, Thomas Jefferson University
Over the last 10 years my laboratory has been involved in biomarker discovery, both at the technical and clinical level. Technically, we have developed methods that allow for the analysis of protein-linked oligosaccharides to identify changes that occur with the development of cancer. Our initial analysis utilized serum for the discovery of biomarkers of primarily liver cancer, also known as hepatocellular carcinoma (HCC). HCC is caused by three main factors: infection of the liver with a hepatotropic virus such as Hepatitis B virus (HBV) or hepatitis C virus (HCV); chronic and excessive alcohol consumption; and now increasingly fatty liver disease. In the USA, liver cancer is associated with 30,000 deaths and worldwide it is estimated that over 700,000 people die every year from HCC, making it the 3rd leading cancer killer. The 5 year survival rate of people with HCC is less than 10%, and is generally attributed to late diagnosis. People caught with early stage HCC can have survival rates of >80%. Thus the key to decreasing the morbidity of HCC, like many other cancers, is early detection.
Our initial finding identified alterations in the glycosylation of liver derived proteins with the development of cancer and through glycoproteomics we identified over 50 proteins that were altered or contained altered glycosylation, in HCC patients. One protein that was altered in HCC was Golgi-protein 73 (GP73). While we have analyzed this protein in a few hundred cancer patients, it has know been examined in over 15,000 patients in over 100 independent studies. This marker has been licensed to Abbott Diagnostics and is being developed for the US market by them. In addition, GP73 is currently available in China, where it is available from several independent companies.
In addition to GP73 we have a number of other biomarkers of liver disease as well as novel technologies that have been patented worldwide and are being developed by Glycotest LLC. Many of these proteins are normal liver protein but which contain altered N-linked glycosylation in cancer. We have developed simple plate based assays to measure these altered glycoforms in blood and use these glycoproteins together with GP73 and other standard clinical factors to better identify those who have cancer.
Our current work involves trying to understand the biological basis of our identified biomarkers as well as new methods and approaches to find better biomarkers. In regards to the first point, the large question regarding many of these glyco-biomarkers is what leads to their increase? The answer, as expected, is complicated. That is, for some of our biomarkers such as increased core fucosylation of N-linked glycans, the increase is the result of an up-regulation in the enzymes responsible for core fucosylation. More importantly, this increase is directly related to activation of signaling through the transcription factor, -catenin. Signaling through the Wnt/-catenin pathway is elevated in 40-60% of HCC cases. This lead to an interesting hypothesis that specific changes in the structure of glycans found on liver proteins, including proteins secreted into the serum, will be correlated with the activation of particular cancer-associated cellular signal transduction pathways. This is now the major focus of our lab and by focusing our studies to the outcome of activating specific cancer-associated signal transduction pathways, many of which have been identified in HCCs, we expect to discover biomarkers that will help refine our understanding of HCC subclasses and provide greater levels of understanding of the molecular changes that are driving the cancer. In preliminary studies, we have identified precise changes in glycosylation that can be observed from the specific hyperactivation of cancer associated pathways such as AKT, MYC, or Hif-1.
In our second approach to find new, more clinically relevant biomarkers, we will utilize a novel method of tissue based glycan imaging that allows for, in situ, both qualitative and quantitative N-linked glycan analysis on tissue using an approach known as matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI). This technique, done in collaboration with Dr. Richard Drake of the Medical University of South Carolina (MUSC) holds promise for the discovery of new molecular markers by examining the N-linked glycan signatures present in tissue and spatially registering output to their point of origin within the tissue. Our central hypothesis is that discrete changes in multiple N-linked glycans in target tissues can reveal mediators of tumor-host interactions involved in cancer initiation and progression, including metastasis, detectable by MALDI-MSI and that these changes will correlate with specific subtypes of cancer.
Selected publication of interest (full list can be found on My Bibliography:
Block, T.M., Comunale, M.A., Romano, P.M, Lowman, M., Fimmel, C., Tennant, B.T., Evans, A., London, W.T., Blumberg, B., Dwek, R.A., Mattu, T.S., Mehta, A. (2005) Targeted glycoproteomics identifies a serum glycoprotein that correlates with liver cancer in woodchucks and people, Proc. Natl. Acad. Sci. USA. 102 (3):779–784.
Comunale, M.A., Krakover, J., Lowman, M., Long, R.E., Philip, R., Seeholzer, S., Evans, A. A., Hann, H.W.L, Block, T.M, Mehta, A.S (2006) Proteomic analysis of serum associated fucosylated glycoproteins in the development of primary hepatocellular carcinoma. Journal of Proteome Research 6(5) -308-315.
Yuanjie Liu, Tianlun Zhou, Ender Simsek, Tim Block, Anand Mehta (2007) A large protein aggregate is partly degraded by resident ER proteases before retro-translocation and degradation by the cytosolic proteasome. Virology. 69(1):69-77.
Mehta AS, Long RE, Comunale MA, Wang M, Rodemich L, Krakover J, Philip R, Marrero JA, Dwek RA, Block TM (2008) Increased levels of galactose-deficient anti-Gal immunoglobulin G in the sera of hepatitis C virus-infected individuals with fibrosis and cirrhosis. J Virology. 82(3):1259-70.
Ashwin Balagopal, Frances H. Philp, Jacquie Astemborski, Timothy M. Block, Anand Mehta, Ronald Long, Gregory D. Kirk, Shruti H. Mehta, Andrea L. Cox, David L. Thomas, Stuart C. Ray (2008) Human immunodeficiency virus-related microbial translocation and progression of hepatitis C. Gastroenterology, 135(1):226-33.
Mengjun Wang, Ronald E. Long, Mary Ann Comunale, Omer Junaidi, Jorge Marrero, Adrian M. Di Bisceglie, Timothy M. Block and Anand S. Mehta (2009) Analysis of GP73 in combination with fucosylated alpha-1-antitrypsin and fucosylated kininogen as a biomarker of hepatocellular carcinoma, Cancer Epidemiology, Biomarkers & Prevention, 18(6):1914-21.
Norton PA, Menne S, Sinnathamby G, Betesh L, Cote PJ, Philip R, Mehta AS, Tennant BC, Block TM. (2010) Glucosidase inhibition enhances presentation of de-N-glycosylated hepatitis B virus epitopes by major histocompatibility complex class I in vitro and in woodchucks. Hepatology. 2010 Oct;52(4):1242-50.
Liu, Y, Block T.M, Mehta, Anand (2011) Discovery of a ubiquitin independent ER associated degradation pathway for the HBV surface protein. PLoS One. 2011;6(9):e24477. Epub 2011 Sep 28.
Romano, P., Mackay, A., Vong, M., deSa, J, Lamontagne A, Comunale, MA., Hafner, J., Block, T.M., Mehta. A.S; Development and application of a recombinant lectin with affinity towards alpha 1,3 linked fucose (2011) Biochem Biophys Res Commun. 2011 Oct 14;414(1):84-9. Epub 2011 Sep 14.
Mehta, A., P. Norton, H. Liang, M.A. Comunale, M. Wang, L. Rodemich-Betesh, A. Koszycki, K. Noda, E. Miyoshi, and T. Block, (2012) Increased Levels of Tetra-antennary N-Linked Glycan but Not Core Fucosylation Are Associated with Hepatocellular Carcinoma Tissue. Cancer Epidemiology, Biomarkers & Prevention : a publication of the American Association for Cancer Research, Published Online First on April 6, 2012; DOI:10.1158/1055-9965.EPI-11-1183.
Chloe L. Thio, Laura Smeaton, Melissa Saulynas, Hyon Hwang, Shanmugam Saravanan, Smita Kulkarni, James Hakim, Mulinda Nyirenda, Hussain Syed Iqbal, Umesh G. Lalloo, Anand Mehta, Kimberly Hollabaugh, Thomas B. Campbell, Shahin Lockman, Judith S. Currier (2012) Characterization of HIV-HBV co-infection in a multi-national HIV-infected cohort, AIDS. Jan 14;27(2):191-201
Mengjun Wang, Timothy M. Block, Jorge Marrero, Adrian M. Di Bisceglie, Karthik Devarajan, and Anand Mehta (2013) A comparison of statistical methods for the detection of hepatocellular carcinoma based on serum biomarkers and clinical variables. BMC Med Genomics. 2013;6 Suppl 3:S9.
Lamontagne A, Long R.E., Comunale M.A., Hafner J., Rodemich L., Di Bisceglie A.M. Marrero J., Block T. and Mehta A. (2013) Increased Levels Anti-Bacterial Antibodies And Markers Of Microbial Exposure Are A Result Of Chronic Hepatitis C Virus Infections And May Be Related To Impaired Liver Function, PLoS One. 2013 Jun 4;8(6):e64992
Powers TW, Jones EE, Betesh LR, Romano P, Gao P, Copland JA, Mehta AS, Drake RR. (2013) A MALDI Imaging Mass Spectrometry Workflow for Spatial Profiling Analysis of N-linked Glycan Expression in Tissues. Analytical Chemistry, Anal Chem. 2013 Oct 15;85(20):9799-806.
Parham Safaie, Maggie Ham, Peter Kuang, Anand Mehta, Mengjun Wang, Adam S Cheifetz, Simon Robson, Daryl Lau, Timothy Block, Alan C Moss (2013) Lectin-Reactive Anti-α-GAL in Patients with Crohn’s Disease; Correlation with Clinical Phenotypes. Inflammatory Bowel Diseases, Dec;19(13):2796-800.
Zhao, X., Guo, F., Comunale, M. A., Mehta, A., Sehgal, M., Jain, P., Cuconati, A., Lin, H., Block, T. M., Chang, J., and Guo, J. T. (2015) Inhibition of endoplasmic reticulum-resident glucosidases impairs severe acute respiratory syndrome coronavirus and human coronavirus NL63 spike protein-mediated entry by altering the glycan processing of angiotensin I-converting enzyme 2. Antimicrob Agents Chemother 59, 206-216.
Wang M, Devarajan K, Singal AG, Marrero JA, Dai J, Feng Z, Rinaudo JA, Srivastava S, Evans A, Hann HW, Lai Y, Yang H, Block TM, Mehta A. (2016) The Doylestown Algorithm: A Test to Improve the Performance of AFP in the Detection of Hepatocellular Carcinoma. Cancer Prev Res (Phila). 9(2):172-9. doi: 10.1158/1940-6207.CAPR-15-0186. Epub 2015 Dec 28.
Anand Mehta, Mary Ann Comunale, Siddhartha Rawat, Jessica C. Casciano, Jason Lamontagne, Harmin Herrera, Aarti Ramanathan, Lucy Betesh, Mengjun Wang, Pamela Norton, Laura F. Steel and Michael J. Bouchard (2016) Intrinsic hepatocyte dedifferentiation is accompanied by upregulation of mesenchymal markers, protein sialylation and core alpha 1,6 linked fucosylation. Nature Scientific Reports. Jun 22;6:27965. doi: 10.1038/srep27965.