Sulfatase 2 (SULF2) Monoclonal Antibody 5D5 Suppresses Human Cholangiocarcinoma Xenograft Growth Through Regulation of a SULF2–Platelet-Derived Growth Factor Receptor Beta–Yes-Associated Protein Signaling Axis
Xin Luo
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
Hepatic Surgery Center and Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Search for more papers by this authorNellie A. Campbell
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
Search for more papers by this authorLi He
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Search for more papers by this authorDaniel R. O'Brien
Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
Search for more papers by this authorMark S. Singer
Department of Anatomy, University of California San Francisco, San Francisco, CA, USA
Search for more papers by this authorHassan Lemjabbar-Alaoui
Department of Anatomy, University of California San Francisco, San Francisco, CA, USA
Search for more papers by this authorKeun Soo Ahn
Department of Surgery, Keimyung University School of Medicine, Keimyung University Dongsan Hospital, Daegu, Republic of Korea
Search for more papers by this authorRory Smoot
Department of Surgery, Mayo Clinic, Rochester, MN, USA
Search for more papers by this authorMichael S. Torbenson
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
Search for more papers by this authorSteven D. Rosen
Department of Anatomy, University of California San Francisco, San Francisco, CA, USA
Search for more papers by this authorCorresponding Author
Lewis R. Roberts
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:
Lewis R. Roberts, M.B., Ch.B., Ph.D.
Division of Gastroenterology and Hepatology, Mayo Clinic
200 First Street SW
Rochester, MN 55905
E-mail: [email protected]
Tel.: +1-507-266-3239
Search for more papers by this authorXin Luo
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
Hepatic Surgery Center and Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Search for more papers by this authorNellie A. Campbell
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
Search for more papers by this authorLi He
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Search for more papers by this authorDaniel R. O'Brien
Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
Search for more papers by this authorMark S. Singer
Department of Anatomy, University of California San Francisco, San Francisco, CA, USA
Search for more papers by this authorHassan Lemjabbar-Alaoui
Department of Anatomy, University of California San Francisco, San Francisco, CA, USA
Search for more papers by this authorKeun Soo Ahn
Department of Surgery, Keimyung University School of Medicine, Keimyung University Dongsan Hospital, Daegu, Republic of Korea
Search for more papers by this authorRory Smoot
Department of Surgery, Mayo Clinic, Rochester, MN, USA
Search for more papers by this authorMichael S. Torbenson
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
Search for more papers by this authorSteven D. Rosen
Department of Anatomy, University of California San Francisco, San Francisco, CA, USA
Search for more papers by this authorCorresponding Author
Lewis R. Roberts
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:
Lewis R. Roberts, M.B., Ch.B., Ph.D.
Division of Gastroenterology and Hepatology, Mayo Clinic
200 First Street SW
Rochester, MN 55905
E-mail: [email protected]
Tel.: +1-507-266-3239
Search for more papers by this authorAbstract
Background and Aims
Existing therapeutic approaches to treat cholangiocarcinoma (CCA) have limited effectiveness, prompting further study to develop therapies for CCA. We report a mechanistic role for the heparan sulfate editing enzyme sulfatase 2 (SULF2) in CCA pathogenesis.
Approach and Results
In silico analysis revealed elevated SULF2 expression in human CCA samples, occurring partly through gain of SULF2 copy number. We examined the effects of knockdown or overexpression of SULF2 on tumor growth, chemoresistance, and signaling pathway activity in human CCA cell lines in vitro. Up-regulation of SULF2 in CCA leads to increased platelet-derived growth factor receptor beta (PDGFRβ)–Yes-associated protein (YAP) signaling activity, promoting tumor growth and chemotherapy resistance. To explore the utility of targeting SULF2 in the tumor microenvironment for CCA treatment, we tested an anti-SULF2 mouse monoclonal antibody, 5D5, in a mouse CCA xenograft model. Targeting SULF2 by monoclonal antibody 5D5 inhibited PDGFRβ–YAP signaling and tumor growth in the mouse xenograft model.
Conclusions
These results suggest that SULF2 monoclonal antibody 5D5 or related agents may be potentially promising therapeutic agents in CCA.
Supporting Information
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| hep31817-sup-0001-Supinfo.pdfPDF document, 2.2 MB | Supplementary Material |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1Rizvi S, Khan SA, Hallemeier CL, Kelley RK, Gores GJ. Cholangiocarcinoma—evolving concepts and therapeutic strategies. Nat Rev Clin Oncol 2018; 15: 95-111.
- 2Banales JM, Marin JJG, Lamarca A, Rodrigues PM, Khan SA, Roberts LR, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol 2020; 17: 557-588.
- 3Clements O, Eliahoo J, Kim JU, Taylor-Robinson SD, Khan SA. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: a systematic review and meta-analysis. J Hepatol 2020; 72: 95-103.
- 4Saha SK, Zhu AX, Fuchs CS, Brooks GA. Forty-year trends in cholangiocarcinoma incidence in the U.S.: intrahepatic disease on the rise. Oncologist 2016; 21: 594-599.
- 5Yang JD, Kim B, Sanderson SO, Sauver JS, Yawn BP, Larson JJ, et al. Biliary tract cancers in Olmsted County, Minnesota, 1976-2008. Am J Gastroenterol 2012; 107: 1256-1262.
- 6Chaiteerakij R, Yang JD, Harmsen WS, Slettedahl SW, Mettler TA, Fredericksen ZS, et al. Risk factors for intrahepatic cholangiocarcinoma: association between metformin use and reduced cancer risk. Hepatology 2013; 57: 648-655.
- 7Bertuccio P, Malvezzi M, Carioli G, Hashim D, Boffetta P, El-Serag HB, et al. Global trends in mortality from intrahepatic and extrahepatic cholangiocarcinoma. J Hepatol 2019; 71: 104-114.
- 8Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 2010; 362: 1273-1281.
- 9Pye DA, Vives RR, Hyde P, Gallagher JT. Regulation of FGF-1 mitogenic activity by heparan sulfate oligosaccharides is dependent on specific structural features: differential requirements for the modulation of FGF-1 and FGF-2. Glycobiology 2000; 10: 1183-1192.
- 10Lin X. Functions of heparan sulfate proteoglycans in cell signaling during development. Development 2004; 131: 6009-6021.
- 11David G, Bai XM, Van der Schueren B, Cassiman JJ, Van den Berghe H. Developmental changes in heparan sulfate expression: in situ detection with mAbs. J Cell Biol 1992; 119: 961-975.
- 12Lai JP, Chien JR, Moser DR, Staub JK, Aderca I, Montoya DP, et al. hSulf1 sulfatase promotes apoptosis of hepatocellular cancer cells by decreasing heparin-binding growth factor signaling. Gastroenterology 2004; 126: 231-248.
- 13Lai J, Chien J, Staub J, Avula R, Greene EL, Matthews TA, et al. Loss of HSulf-1 up-regulates heparin-binding growth factor signaling in cancer. J Biol Chem 2003; 278: 23107-23117.
- 14Lai JP, Sandhu DS, Shire AM, Roberts LR. The tumor suppressor function of human sulfatase 1 (SULF1) in carcinogenesis. J Gastrointest Cancer 2008; 39: 149-158.
- 15Shire A, Lomberk G, Lai JP, Zou H, Tsuchiya N, Aderca I, et al. Restoration of epigenetically silenced SULF1 expression by 5-aza-2-deoxycytidine sensitizes hepatocellular carcinoma cells to chemotherapy-induced apoptosis. Med Epigenet 2015; 3: 1-18.
- 16Yang JD, Sun Z, Hu C, Lai J, Dove R, Nakamura I, et al. Sulfatase 1 and sulfatase 2 in hepatocellular carcinoma: associated signaling pathways, tumor phenotypes, and survival. Genes Chromosomes Cancer 2011; 50: 122-135.
- 17Dhanasekaran R, Nakamura I, Hu C, Chen G, Oseini AM, Seven ES, et al. Activation of the transforming growth factor-beta/SMAD transcriptional pathway underlies a novel tumor-promoting role of sulfatase 1 in hepatocellular carcinoma. Hepatology 2015; 61: 1269-1283.
- 18Lai JP, Oseini AM, Moser CD, Yu C, Elsawa SF, Hu C, et al. The oncogenic effect of sulfatase 2 in human hepatocellular carcinoma is mediated in part by glypican 3-dependent Wnt activation. Hepatology 2010; 52: 1680-1689.
- 19Lai JP, Sandhu DS, Yu C, Han T, Moser CD, Jackson KK, et al. Sulfatase 2 up-regulates glypican 3, promotes fibroblast growth factor signaling, and decreases survival in hepatocellular carcinoma. Hepatology 2008; 47: 1211-1222.
- 20Zheng X, Gai X, Han S, Moser CD, Hu C, Shire AM, et al. The human sulfatase 2 inhibitor 2,4-disulfonylphenyl-tert-butylnitrone (OKN-007) has an antitumor effect in hepatocellular carcinoma mediated via suppression of TGFB1/SMAD2 and Hedgehog/GLI1 signaling. Genes Chromosomes Cancer 2013; 52: 225-236.
- 21Carr RM, Romecin Duran PA, Tolosa EJ, Ma C, Oseini AM, Moser CD, et al. The extracellular sulfatase SULF2 promotes liver tumorigenesis by stimulating assembly of a promoter-looping GLI1-STAT3 transcriptional complex. J Biol Chem 2020; 295: 2698-2712.
- 22Chen G, Nakamura I, Dhanasekaran R, Iguchi E, Tolosa EJ, Romecin PA, et al. Transcriptional induction of periostin by a sulfatase 2-TGFbeta1-SMAD signaling axis mediates tumor angiogenesis in hepatocellular carcinoma. Cancer Res 2017; 77: 632-645.
- 23Singer MS, Phillips JJ, Lemjabbar-Alaoui H, Wang YQ, Wu J, Goldman R, et al. SULF2, a heparan sulfate endosulfatase, is present in the blood of healthy individuals and increases in cirrhosis. Clin Chim Acta 2015; 440: 72-78.
- 24Ahn KS, O'Brien D, Kang YN, Mounajjed T, Kim YH, Kim TS, et al. Prognostic subclass of intrahepatic cholangiocarcinoma by integrative molecular-clinical analysis and potential targeted approach. Hepatol Int 2019; 13: 490-500.
- 25Goldman MJ, Craft B, Hastie M, Repecka K, McDade F, Kamath A, et al. Visualizing and interpreting cancer genomics data via the Xena platform. Nat Biotechnol 2020; 38: 675-678.
- 26Ding X, Chaiteerakij R, Moser CD, Shaleh H, Boakye J, Chen G, et al. Antitumor effect of the novel sphingosine kinase 2 inhibitor ABC294640 is enhanced by inhibition of autophagy and by sorafenib in human cholangiocarcinoma cells. Oncotarget 2016; 7: 20080-20092.
- 27Leiting JL, Murphy SJ, Bergquist JR, Hernandez MC, Ivanics T, Abdelrahman AM, et al. Biliary tract cancer patient-derived xenografts: surgeon impact on individualized medicine. JHEP Rep 2020; 2:100068.
- 28Piccolo S, Dupont S, Cordenonsi M. The biology of YAP/TAZ: hippo signaling and beyond. Physiol Rev 2014; 94: 1287-1312.
- 29Smoot RL, Werneburg NW, Sugihara T, Hernandez MC, Yang L, Mehner C, et al. Platelet-derived growth factor regulates YAP transcriptional activity via Src family kinase dependent tyrosine phosphorylation. J Cell Biochem 2018; 119: 824-836.
- 30Lai JP, Chien J, Strome SE, Staub J, Montoya DP, Greene EL, et al. HSulf-1 modulates HGF-mediated tumor cell invasion and signaling in head and neck squamous carcinoma. Oncogene 2004; 23: 1439-1447.
- 31Li J, Kleeff J, Abiatari I, Kayed H, Giese NA, Felix K, et al. Enhanced levels of Hsulf-1 interfere with heparin-binding growth factor signaling in pancreatic cancer. Mol Cancer 2005; 4:14.
- 32Lee JS, Heo J, Libbrecht L, Chu IS, Kaposi-Novak P, Calvisi DF, et al. A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells. Nat Med 2006; 12: 410-416.
- 33Uchimura K, Morimoto-Tomita M, Bistrup A, Li J, Lyon M, Gallagher J, et al. HSulf-2, an extracellular endoglucosamine-6-sulfatase, selectively mobilizes heparin-bound growth factors and chemokines: effects on VEGF, FGF-1, and SDF-1. BMC Biochem 2006; 7:2.
- 34Pan D. Hippo signaling in organ size control. Genes Dev 2007; 21: 886-897.
- 35Fan R, Kim NG, Gumbiner BM. Regulation of Hippo pathway by mitogenic growth factors via phosphoinositide 3-kinase and phosphoinositide-dependent kinase-1. Proc Natl Acad Sci U S A 2013; 110: 2569-2574.
- 36Smith EM, Mitsi M, Nugent MA, Symes K. PDGF-A interactions with fibronectin reveal a critical role for heparan sulfate in directed cell migration during Xenopus gastrulation. Proc Natl Acad Sci U S A 2009; 106: 21683-21688.
- 37Abramsson A, Kurup S, Busse M, Yamada S, Lindblom P, Schallmeiner E, et al. Defective N-sulfation of heparan sulfate proteoglycans limits PDGF-BB binding and pericyte recruitment in vascular development. Genes Dev 2007; 21: 316-331.
- 38Rolny C, Spillmann D, Lindahl U, Claesson-Welsh L. Heparin amplifies platelet-derived growth factor (PDGF)-BB-induced PDGF alpha-receptor but not PDGF beta-receptor tyrosine phosphorylation in heparan sulfate-deficient cells. Effects on signal transduction and biological responses. J Biol Chem 2002; 277: 19315-19321.
- 39Ball SG, Shuttleworth CA, Kielty CM. Vascular endothelial growth factor can signal through platelet-derived growth factor receptors. J Cell Biol 2007; 177: 489-500.
- 40Malmstrom J, Westergren-Thorsson G. Heparan sulfate upregulates platelet-derived growth factor receptors on human lung fibroblasts. Glycobiology 1998; 8: 1149-1155.
- 41Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med 2013; 19: 1423-1437.
- 42Dhoot GK, Gustafsson MK, Ai X, Sun W, Standiford DM, Emerson CP Jr. Regulation of Wnt signaling and embryo patterning by an extracellular sulfatase. Science 2001; 293: 1663-1666.
- 43Xu D, Fuster MM, Lawrence R, Esko JD. Heparan sulfate regulates VEGF165- and VEGF121-mediated vascular hyperpermeability. J Biol Chem 2011; 286: 737-745.
- 44Hossain MM, Hosono-Fukao T, Tang R, Sugaya N, van Kuppevelt TH, Jenniskens GJ, et al. Direct detection of HSulf-1 and HSulf-2 activities on extracellular heparan sulfate and their inhibition by PI-88. Glycobiology 2010; 20: 175-186.
- 45Chhabra M, Ferro V. PI-88 and related heparan sulfate mimetics. Adv Exp Med Biol 2020; 1221: 473-491.
Author names in bold designate shared co-first authorship.
