Research Summary

I have a longstanding interest in biological sulfation and its roles in immunology and cancer. The origin of this interest began 40 years ago with our investigation of molecular mechanisms involved in lymphocyte homing to lymph nodes. Our early experiments established that lymphocyte attachment to high endothelial venules (HEVs) in lymph nodes involves a calcium-dependent lectin-like receptor on lymphocytes and carbohydrate-based ligands displayed on HEVs. With Genentech, we cloned the receptor, now known as L-selectin and found a C-type lectin domain, thus confirming its lectin nature. This work inaugurated the elucidation of the selectin family, which is comprised of E- and P-selectin, as well as L-selectin. We went on to define the HEV-ligands for L-selectin and showed that they are mucin-like glycoproteins that express O-glycans with 6-sulfo sialyl Lewis x as the key recognition determinant. We also identified the critical HEV-associated sulfotransferases that elaborate the essential sulfation modifications of the ligands. HEVs with the same biochemical phenotype as in lymph nodes are also found in tertiary lymphoid organs (TLOs) that are associated with tumors. The presence of HEVs in tumor-associated TLOs is correlated with good outcomes for patients with breast cancer and melanoma, probably reflecting immune-protection by the TLOs that are in proximity to the tumors and highlighting the importance of our elucidation of fundamental mechanisms of lymphocyte-HEV interactions.

Our study of the sulfatases known as the SULFs (SULF1 and SULF2) represent an extension of my interest in the regulation of sulfation at the cell surface. We originally cloned the human and mouse versions of these enzymes. We demonstrated that these enzymes are secreted and act as neutral pH glucosamine 6-O-endosulfatases for the GAG chains of heparan sulfate proteoglycans (HSPGs). By removing 6OS groups from glucosamines in GAG chains, the SULF are able to mobilize growth factors/chemokines/morphogens from HS sequestration and modulate multiple signaling pathways in the cells, including canonical Wnt, TGF-beta, and PDGF signaling. The two SULFs are over-expressed in multiple cancers at the mRNA and protein levels. For several of these cancers, SULF2 levels are associated with poor clinical outcomes. Our studies were the first to implicate SULF2 as an oncogenic driver in pancreatic cancer, NSCLC and glioma (with Joanna Phillips and Zena Werb). Subsequent studies have shown pro-oncogenic roles for SULF2 in hepatocellular carcinoma, neuroblastoma, breast cancer, cervical cancer, and colorectal cancer. We have developed function-blocking mAbs against human/mouse SULF2, which will allow further in vitro and in vivo investigation of the oncogenic activities of this enzyme.

Since SULF2 is secreted and is overexpressed in multiple cancers, this protein may have utility as a diagnostic or prognostic biomarker. We have developed a sensitive capture ELISA for SULF2 and have detected the enzyme in human blood and body fluids. Preliminary evidence obtained with the ELISA indicates overexpression of SULF2 in mouth-wash samples of patients with head & neck squamous cell carcinoma. Ongoing collaborations are aimed at determining the biomarker utility of SULF2 in several cancers.

Research Funding

  • March 1, 1982 - May 31, 2015 - Bio-Organic Biomedical Mass Spectrometry Resource, Co-Investigator. Sponsor: NIH, Sponsor Award ID: P41RR001614
  • August 1, 1992 - July 31, 2012 - Cell Surface Lectins and Intercellular Adhesion, Principal Investigator. Sponsor: NIH/NIGMS, Sponsor Award ID: R01GM023547
  • July 1, 2006 - June 30, 2009 - Role of Heparan Sulfate-Degrading Sulfatases in Pancreatic Adenocarcinomas, Principal Investigator. Sponsor: NIH/NCI, Sponsor Award ID: R21CA122025
  • September 1, 2009 - September 24, 2008 - Mucosal Immune Barrier in Infection and Immunity, Co-Investigator. Sponsor: NIH/NIAID, Sponsor Award ID: P01AI053194

Education

University of California, Berkeley, CA, B.A., 1966, Physics
Cornell University, Ithaca, NY, Ph.D., 1972, Neurobiology
University of California, San Diego, CA, Postdoc, 1972-76, Cell Biology

Honors & Awards

  • 1962
    University of California Regents Scholar
  • 1966
    Phi Beta Kappa
  • 1966
    Phi Kappa Phi
  • 1966- 1968
    American Cancer Society Postdoctoral Fellowship
  • 1977-1982
    NIH Career Development Award
  • 1993
    Feulgen Lecture
  • 1994
    Keynote address to Keystone Symposium on Complex Carbohydrates in Biology & Medicine
  • 1996-2006
    NIH Merit Award
  • 2005
    Keynote Speaker at Keynote Conference on Leukocyte Trafficking
  • 2006
    Ernest Witebsky Memorial Lecture, SUNY, Buffalo, NY
  • 2007
    Elected AAAS Fellow
  • 2010
    Karl Meyer Award from Society for Glycobiology

Selected Publications

  1. Luo X, Campbell NA, He L, O'Brien DR, Singer MS, Lemjabbar-Alaoui H, Ahn KS, Smoot R, Torbenson MS, Rosen SD, Roberts LR SULF2 monoclonal antibody 5D5 suppresses human cholangiocarcinoma xenograft growth via regulation of a SULF2-PDGFRβ-YAP signaling axis.  View on PubMed
  2. Caserta E, Chea J, Minnix M, Poku EK, Viola D, Vonderfecht S, Yazaki P, Crow D, Khalife J, Sanchez JF, Palmer JM, Hui S, Carlesso N, Keats J, Kim Y, Buettner R, Marcucci G, Rosen S, Shively J, Colcher D, Krishnan A, Pichiorri F Copper 64-labeled daratumumab as a PET/CT imaging tracer for multiple myeloma.  View on PubMed
  3. Flowers SA, Zhou X, Wu J, Wang Y, Makambi K, Kallakury BV, Singer MS, Rosen SD, Davidson B, Goldman R Expression of the extracellular sulfatase SULF2 is associated with squamous cell carcinoma of the head and neck.  View on PubMed
  4. Singer MS, Phillips JJ, Lemjabbar-Alaoui H, Wang YQ, Wu J, Goldman R, Rosen SD SULF2, a heparan sulfate endosulfatase, is present in the blood of healthy individuals and increases in cirrhosis.  View on PubMed
  5. Rosen SD, Daneman R High endothelial venules through a transcriptomics lens.  View on PubMed
  6. Patnode ML, Bando JK, Krummel MF, Locksley RM, Rosen SD Leukotriene B4 amplifies eosinophil accumulation in response to nematodes.  View on PubMed
  7. Maltseva I, Chan M, Kalus I, Dierks T, Rosen SD The SULFs, extracellular sulfatases for heparan sulfate, promote the migration of corneal epithelial cells during wound repair.  View on PubMed
  8. Patnode ML, Cheng CW, Chou CC, Singer MS, Elin MS, Uchimura K, Crocker PR, Khoo KH, Rosen SD Galactose 6-O-sulfotransferases are not required for the generation of Siglec-F ligands in leukocytes or lung tissue.  View on PubMed
  9. Patnode ML, Yu SY, Cheng CW, Ho MY, Tegesjö L, Sakuma K, Uchimura K, Khoo KH, Kannagi R, Rosen SD KSGal6ST generates galactose-6-O-sulfate in high endothelial venules but does not contribute to L-selectin-dependent lymphocyte homing.  View on PubMed
  10. Lui NS, van Zante A, Rosen SD, Jablons DM, Lemjabbar-Alaoui H SULF2 expression by immunohistochemistry and overall survival in oesophageal cancer: a cohort study.  View on PubMed
  11. Zhang Y, Chen YC, Krummel MF, Rosen SD Autotaxin through lysophosphatidic acid stimulates polarization, motility, and transendothelial migration of naive T cells.  View on PubMed
  12. Phillips JJ, Huillard E, Robinson AE, Ward A, Lum DH, Polley MY, Rosen SD, Rowitch DH, Werb Z Heparan sulfate sulfatase SULF2 regulates PDGFRa signaling and growth in human and mouse malignant glioma.  View on PubMed
  13. Lee SM, Rosen S, Weinstein P, van Rooijen N, Noble-Haeusslein LJ Prevention of both neutrophil and monocyte recruitment promotes recovery after spinal cord injury.  View on PubMed
  14. Arata-Kawai H, Singer MS, Bistrup A, Zante Av, Wang YQ, Ito Y, Bao X, Hemmerich S, Fukuda M, Rosen SD Functional contributions of N- and O-glycans to L-selectin ligands in murine and human lymphoid organs.  View on PubMed
  15. Rosen SD, Lemjabbar-Alaoui H Sulf-2: an extracellular modulator of cell signaling and a cancer target candidate.  View on PubMed
  16. Uchimura K, Lemjabbar-Alaoui H, van Kuppevelt TH, Rosen SD Use of a phage display antibody to measure the enzymatic activity of the Sulfs.  View on PubMed
  17. Hossain MM, Hosono-Fukao T, Tang R, Sugaya N, van Kuppevelt TH, Jenniskens GJ, Kimata K, Rosen SD, Uchimura K Direct detection of HSulf-1 and HSulf-2 activities on extracellular heparan sulfate and their inhibition by PI-88.  View on PubMed
  18. Rosen SD, Arata-Kawai H "Home sweet home" for lymphocytes.  View on PubMed
  19. Tang R, Rosen SD Functional consequences of the subdomain organization of the sulfs.  View on PubMed
  20. Kerr SC, Fieger CB, Snapp KR, Rosen SD Endoglycan, a member of the CD34 family of sialomucins, is a ligand for the vascular selectins.  View on PubMed

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