Targeting Human Cancer by a Glycosaminoglycan Binding Malaria Protein

Ali Salanti, Thomas M. Clausen, Mette O. Agerbæk, Nader Al Nakouzi, Madeleine Dahlbäck, Htoo Z. Oo, Sherry Lee, Tobias Gustavsson, Jamie R. Rich, Bradley J. Hedberg, Yang Mao, Line Barington, Marina A. Pereira, Janine LoBello, Makoto Endo, Ladan Fazli, Jo Soden, Chris K. Wang, Adam F. Sander, Robert DagilSusan Thrane, Peter J. Holst, Le Meng, Francesco Favero, Glen J. Weiss, Morten A. Nielsen, Jim Freeth, Torsten O. Nielsen, Joseph Zaia, Nhan L. Tran, Jeff Trent, John S. Babcook, Thor G. Theander, Poul H. Sorensen, Mads Daugaard

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Abstract

Plasmodium falciparum engineer infected erythrocytes to present the malarial protein, VAR2CSA, which binds a distinct type chondroitin sulfate (CS) exclusively expressed in the placenta. Here, we show that the same CS modification is present on a high proportion of malignant cells and that it can be specifically targeted by recombinant VAR2CSA (rVAR2). In tumors, placental-like CS chains are linked to a limited repertoire of cancer-associated proteoglycans including CD44 and CSPG4. The rVAR2 protein localizes to tumors in vivo and rVAR2 fused to diphtheria toxin or conjugated to hemiasterlin compounds strongly inhibits in vivo tumor cell growth and metastasis. Our data demonstrate how an evolutionarily refined parasite-derived protein can be exploited to target a common, but complex, malignancy-associated glycosaminoglycan modification.

Original languageEnglish
Article number2143
Pages (from-to)500-514
Number of pages15
JournalCancer Cell
Volume28
Issue number4
DOIs
Publication statusPublished - Oct 12 2015

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All Science Journal Classification (ASJC) codes

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Salanti, A., Clausen, T. M., Agerbæk, M. O., Al Nakouzi, N., Dahlbäck, M., Oo, H. Z., ... Daugaard, M. (2015). Targeting Human Cancer by a Glycosaminoglycan Binding Malaria Protein. Cancer Cell, 28(4), 500-514. [2143]. https://doi.org/10.1016/j.ccell.2015.09.003