Proteoglycans and Cancer Biology

PDAC We remain interested in the role of proteoglycans in tumor formation, angiogenesis and metastasis. We were the first group to show that tumor formation depends on heparan sulfate in CHO cells, which has been subsequently confirmed in other types of cancer. We also showed that endothelial heparan sulfate was crucial in pathological tumor angiogenesis. Ongoing studies focus on a novel form of heparan sulfate produced by pancreatic adenocarcinoma that can also be detected in plasma in mice and humans. Studies show an amazing correlation of these biomarkers and survival in patients. Efforts are underway to determine its utility as a biomarker for early diagnosis and its functional significance in terms of tumor growth, invasion and metastasis.

Another ongoing area of interest is osteochondroma formation characteristic of a pediatric disease called hereditary multiple exostosis. This disorder is characterized by benign osteochondromas that arise on the growth plates of bones formed by endochondral ossification. The disease is caused by heterozygous mutations in Ext genes, which encode the heparan sulfate copolymerase. Efforts are underway to find small molecules that reverse the disease and to identify other genes that modulate heparan sulfate assembly.

Relevant Papers

Esko, J.D., Rostand, K.S., and Weinke, J.L. (1988) Tumor formation dependent on proteoglycan biosynthesis. Science 241:1092-1096. PMID:3137658

Belting, M, Borsig, L., Fuster, M., Brown, JR, Persson, L., Fransson, L.-Å., and Esko, J.D. (2002) Tumor attenuation by combined heparan sulfate and polyamine depletion. Proc. Natl. Acad. Sci USA 99:371-376. PMID:11752393 PMCID:117567

Fuster, M.M., Brown, J.R., Wang, L, and Esko, J.D. (2003) A disaccharide precursor of sialyl Lewis X inhibits metastatic potential of tumor cells. Cancer Res. 63:2775-2781. PMID:12782582

Stickens, D., Zak, B.M., Rougier, N., Esko, J.D., Werb, Z. (2005) Mice deficient in Ext2 lack heparan sulfate and develop exostoses. Development 132:5055-5068. PMID:16236767, PMCID:2767329

Zak, B.M., Schuksz, M., Koyama, E., Mundy, C., Wells, D.E., Yamaguchi, Y., Pacifici, M., and Esko, J.D. (2011) Compound heterozygous loss of Ext1 and Ext2 is sufficient for formation of multiple exostoses in mouse ribs and long bones. Bone 48:979-987. PMID:21310272 PMCID:3335264

Spinler, K., Bajaj, J., Ito, T., Zimdahl, B., Hamilton, M., Ahmadi, A., Koechlein, C., Lytle, N., Kwon, H.Y., Anower-E-Khuda, F., Sun, H., Blevins, A., Weeks, J., Kritzik, M., Karlseder, J., Park, P.W., Ginsberg, M., Esko, J.D. and Reya, T. (2020) A stem cell reporter based platform to identify and target drug resistant stem cells in myeloid leukemia. Nat. Comm11:5998. PMID:33243988

Spliid, C.B., Toledo, A.G., Sanderson, P., Mao, Y., Gatto, F., Gustavsson, T., Choudhary, S., Saldanha, A.L., Vogelsang, R.P., Gögenur, I., Theander, T.G., Leach, F.E. 3rd, Amster, I.J., Esko, J.D., Salanti, A., Clausen, T.M. (2021) The specificity of the malarial VAR2CSA protein for chondroitin sulfate depends on 4-O-sulfation and ligand accessibility. J. Biol. Chem. 297(6):101391. PMID:34762909

Oo, H.Z., Lohinai, Z., Khazamipour, N., Lo, J., Kumar, G., Pihl, J., Adomat, H., Nabavi, N., Behmanesh, H., Zhai, B., Dagil, R., Choudhary, S., Gustavsson, T., Clausen, T.M., Esko, J.D., Allen, J.W., Thompson, M.A., Tran, N.L., Moldvay, J., Dome, B., Salanti, A., Al-Nakouzi, N., Weiss, G.J., Daugaard, M. (2021) Oncofetal chondroitin sulfate is a highly expressed therapeutic target in non-small cell lung cancer. Cancers (Basel) 3:4489. PMID:34503301