Principal Investigator

Anand S
Awardee Organization

Medical University Of South Carolina
United States

Fiscal Year
Activity Code
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

Glycopathology of HCC: identification of the source cells of serum fucosylation

In the Annual Report to the Nation on the Status of Cancer, mortality from Hepatocellular carcinoma (HCC) increased at an annual rate of 2.8% in men and 2.2% in women, making it the cancer with the greatest increase in mortality in the United States (USA) over the last 10 years. The occurrence of liver cancer is predicted to continue rising in the USA and will exceed 50,000 cases by 2021. The majority of HCC arises in the background of liver fibrosis and cirrhosis, usually associated with chronic viral infection (hepatitis B and hepatitis C virus) or nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) associated with obesity. Our laboratory has shown alterations in both core and outer-arm fucosylation in HCC. These glycan modifications have promise as biomarkers of cancer and are actively being commercialized by a number of groups (including us). We have a developed a diagnostic panel that is comprised of clinical data along with one additional novel biomarker, fucosylated kininogen, that dramatically improves upon the detection of HCC, and in particular, the identification of those with early stage HCC. In an effort to identify the source of fucosylated serum glycoprotein, we have developed a novel method for tissue-based glycan analysis. In an analysis of 145 HCC tissue and 112 adjacent control or cirrhotic tissue control samples, we have identified two major changes in the N-linked glycan family that are associated with HCC. The first change observed was increased levels of fucosylation, a modification also often observed in serum of patients with HCC. However, ~50% of the tissue samples analyzed had no increase in fucose. Often these tumors without increased fucosylation had increases in tetra-antennary glycan. We hypothesize that the genetic heterogeneity of the tumor might have an impact upon the glycan heterogeneity in the tissue and serum. Consequently, the glycans may not only be used as biomarkers for the early detection of cancer but offer information into the specific genetics of the cancer. In this application, we will link the glycomic changes observed in both tissue and serum with the underlying genetic changes. As we will have matching tissue and serum, we will be able to determine if our current biomarker panel is capable of identifying fucose negative HCC. Lastly, we will utilize several proteomic and glycomic methods to identify biomarkers for cancer without increased levels of fucosylation.


  • Angel PM, Saunders J, Clift CL, White-Gilbertson S, Voelkel-Johnson C, Yeh E, Mehta A, Drake RR. A Rapid Array-Based Approach to N-Glycan Profiling of Cultured Cells. Journal of proteome research. 2019 Oct 4;18(10):3630-3639. Epub 2019 Sep 19. PMID: 31535553
  • Fujiwara N, Singal AG, Hoshida Y. Dose and Duration of Aspirin Use to Reduce Incident Hepatocellular Carcinoma. Hepatology (Baltimore, Md.). 2019 Dec;70(6):2216-2217. Epub 2019 Aug 7. PMID: 31206214
  • Clift CL, Drake RR, Mehta A, Angel PM. Multiplexed imaging mass spectrometry of the extracellular matrix using serial enzyme digests from formalin-fixed paraffin-embedded tissue sections. Analytical and bioanalytical chemistry. 2021 Apr;413(10):2709-2719. Epub 2020 Nov 18. PMID: 33206215
  • West CA, Liang H, Drake RR, Mehta AS. New Enzymatic Approach to Distinguish Fucosylation Isomers of N-Linked Glycans in Tissues Using MALDI Imaging Mass Spectrometry. Journal of proteome research. 2020 Aug 7;19(8):2989-2996. Epub 2020 Jun 8. PMID: 32441096
  • DelaCourt A, Black A, Angel P, Drake R, Hoshida Y, Singal A, Lewin D, Taouli B, Lewis S, Schwarz M, Fiel MI, Mehta AS. N-Glycosylation Patterns Correlate with Hepatocellular Carcinoma Genetic Subtypes. Molecular cancer research : MCR. 2021 Nov;19(11):1868-1877. Epub 2021 Aug 11. PMID: 34380744
  • Scott DA, Casadonte R, Cardinali B, Spruill L, Mehta AS, Carli F, Simone N, Kriegsmann M, Del Mastro L, Kriegsmann J, Drake RR. Increases in Tumor N-Glycan Polylactosamines Associated with Advanced HER2-Positive and Triple-Negative Breast Cancer Tissues. Proteomics. Clinical applications. 2019 Jan;13(1):e1800014. PMID: 30592377
  • Ochoa-Rios S, O'Connor IP, Kent LN, Clouse JM, Hadjiyannis Y, Koivisto C, Pecot T, Angel PM, Drake RR, Leone G, Mehta AS, Rockey DC. Imaging Mass Spectrometry Reveals Alterations in N-Linked Glycosylation That Are Associated With Histopathological Changes in Nonalcoholic Steatohepatitis in Mouse and Human. Molecular & cellular proteomics : MCP. 2022 May;21(5):100225. Epub 2022 Mar 22. PMID: 35331917
  • Fujiwara N, Kobayashi M, Fobar AJ, Hoshida A, Marquez CA, Koneru B, Panda G, Taguri M, Qian T, Raman I, Li QZ, Hoshida H, Sezaki H, Kumada H, Tateishi R, Yokoo T, Yopp AC, Chung RT, Fuchs BC, Baumert TF, Marrero JA, Parikh ND, Zhu S, Singal AG, Hoshida Y. A blood-based prognostic liver secretome signature and long-term hepatocellular carcinoma risk in advanced liver fibrosis. Med (New York, N.Y.). 2021 Jul 9;2(7):836-850.e10. Epub 2021 Apr 21. PMID: 34318286
  • Lee YT, Fujiwara N, Yang JD, Hoshida Y. Risk stratification and early detection biomarkers for precision HCC screening. Hepatology (Baltimore, Md.). 2022 Sep 9. Epub 2022 Sep 9. PMID: 36082510
  • Zhu S, Kubota N, Hoshida Y. Transcriptome-Guided Design of Physiological Multilineage Liver Organoids. Trends in genetics : TIG. 2021 May;37(5):403-404. Epub 2021 Feb 1. PMID: 33541711
  • Singal AG, Hoshida Y, Pinato DJ, Marrero J, Nault JC, Paradis V, Tayob N, Sherman M, Lim YS, Feng Z, Lok AS, Rinaudo JA, Srivastava S, Llovet JM, Villanueva A. International Liver Cancer Association (ILCA) White Paper on Biomarker Development for Hepatocellular Carcinoma. Gastroenterology. 2021 Jun;160(7):2572-2584. Epub 2021 Mar 9. PMID: 33705745
  • Scott DA, Wang M, Grauzam S, Pippin S, Black A, Angel PM, Drake RR, Castellino S, Kono Y, Rockey DC, Mehta AS. GlycoFibroTyper: A Novel Method for the Glycan Analysis of IgG and the Development of a Biomarker Signature of Liver Fibrosis. Frontiers in immunology. 2022 Feb 7;13:797460. doi: 10.3389/fimmu.2022.797460. eCollection 2022. PMID: 35197973
  • Baumert TF, Hoshida Y. Addressing the Challenges of Hepatitis C Cure and Persistent Risk of Hepatocellular Carcinoma. Viruses. 2019 May 15;11. (5). PMID: 31096600
  • Blaschke CRK, McDowell CT, Black AP, Mehta AS, Angel PM, Drake RR. Glycan Imaging Mass Spectrometry: Progress in Developing Clinical Diagnostic Assays for Tissues, Biofluids, and Cells. Clinics in laboratory medicine. 2021 Jun;41(2):247-266. Epub 2021 Apr 24. PMID: 34020762
  • West CA, Wang M, Herrera H, Liang H, Black A, Angel PM, Drake RR, Mehta AS. N-Linked Glycan Branching and Fucosylation Are Increased Directly in Hcc Tissue As Determined through in Situ Glycan Imaging. Journal of proteome research. 2018 Oct 5;17(10):3454-3462. Epub 2018 Sep 5. PMID: 30110170
  • Blaschke CRK, Black AP, Mehta AS, Angel PM, Drake RR. Rapid N-Glycan Profiling of Serum and Plasma by a Novel Slide-Based Imaging Mass Spectrometry Workflow. Journal of the American Society for Mass Spectrometry. 2020 Dec 2;31(12):2511-2520. Epub 2020 Aug 18. PMID: 32809822
  • Black AP, Angel PM, Drake RR, Mehta AS. Antibody Panel Based N-Glycan Imaging for N-Glycoprotein Biomarker Discovery. Current protocols in protein science. 2019 Dec;98(1):e99. PMID: 31721442
  • Fujiwara N, Qian T, Koneru B, Hoshida Y. Omics-derived hepatocellular carcinoma risk biomarkers for precision care of chronic liver diseases. Hepatology research : the official journal of the Japan Society of Hepatology. 2020 Jul;50(7):817-830. Epub 2020 May 15. PMID: 32323426
  • Drake RR, McDowell C, West C, David F, Powers TW, Nowling T, Bruner E, Mehta AS, Angel PM, Marlow LA, Tun HW, Copland JA. Defining the human kidney N-glycome in normal and cancer tissues using MALDI imaging mass spectrometry. Journal of mass spectrometry : JMS. 2020 Apr;55(4):e4490. Epub 2020 Jan 21. PMID: 31860772
  • Singal AG, Tayob N, Mehta A, Marrero JA, Jin Q, Lau J, Parikh ND. Doylestown Plus and GALAD Demonstrate High Sensitivity for HCC Detection in Patients With Cirrhosis. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2022 Apr;20(4):953-955.e2. Epub 2021 Apr 20. PMID: 33864933
  • Qin J, Higashi T, Nakagawa S, Fujiwara N, Yamashita YI, Beppu T, Baba H, Kobayashi M, Kumada H, Gunasekaran G, Schiano TD, Thung SN, Fiel MI, Hoshida Y, Ward SC. Steatohepatitic Variant of Hepatocellular Carcinoma Is Associated With Both Alcoholic Steatohepatitis and Nonalcoholic Steatohepatitis: A Study of 2 Cohorts With Molecular Insights. The American journal of surgical pathology. 2020 Oct;44(10):1406-1412. PMID: 32618599
  • Black AP, Liang H, West CA, Wang M, Herrera HP, Haab BB, Angel PM, Drake RR, Mehta AS. A Novel Mass Spectrometry Platform for Multiplexed N-Glycoprotein Biomarker Discovery from Patient Biofluids by Antibody Panel Based N-Glycan Imaging. Analytical chemistry. 2019 Jul 2;91(13):8429-8435. Epub 2019 Jun 20. PMID: 31177770
  • McDowell CT, Lu X, Mehta AS, Angel PM, Drake RR. Applications and continued evolution of glycan imaging mass spectrometry. Mass spectrometry reviews. 2023 Mar;42(2):674-705. Epub 2021 Aug 15. PMID: 34392557
  • Fujiwara N, Kubota N, Crouchet E, Koneru B, Marquez CA, Jajoriya AK, Panda G, Qian T, Zhu S, Goossens N, Wang X, Liang S, Zhong Z, Lewis S, Taouli B, Schwartz ME, Fiel MI, Singal AG, Marrero JA, Fobar AJ, Parikh ND, Raman I, Li QZ, Taguri M, Ono A, Aikata H, Nakahara T, Nakagawa H, Matsushita Y, Tateishi R, Koike K, Kobayashi M, Higashi T, Nakagawa S, Yamashita YI, Beppu T, Baba H, Kumada H, Chayama K, Baumert TF, Hoshida Y. Molecular signatures of long-term hepatocellular carcinoma risk in nonalcoholic fatty liver disease. Science translational medicine. 2022 Jun 22;14(650):eabo4474. Epub 2022 Jun 22. PMID: 35731891
  • Singal AG, Tayob N, Mehta A, Marrero JA, El-Serag H, Jin Q, Saenz de Viteri C, Fobar A, Parikh ND. GALAD demonstrates high sensitivity for HCC surveillance in a cohort of patients with cirrhosis. Hepatology (Baltimore, Md.). 2022 Mar;75(3):541-549. Epub 2021 Dec 17. PMID: 34618932
  • Fujiwara N, Hoshida Y. Viral Exposure Signature Associated with Liver Cancer Risk. Trends in molecular medicine. 2020 Aug;26(8):711-713. Epub 2020 Jul 10. PMID: 32654969