Heparan-6-O-Endosulfatase 2 Promotes Invasiveness of Head and Neck Squamous Carcinoma Cell Lines in Co-Cultures with Cancer-Associated Fibroblasts

Author:

Mukherjee Pritha1ORCID,Zhou Xin12,Benicky Julius13,Panigrahi Aswini13,Aljuhani Reem34,Liu Jian5,Ailles Laurie67,Pomin Vitor H.89ORCID,Wang Zhangjie10,Goldman Radoslav134ORCID

Affiliation:

1. Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA

2. Biotechnology Program, Northern Virginia Community College, Manassas, VA 20109, USA

3. Clinical and Translational Glycoscience Research Center, Georgetown University, Washington, DC 20057, USA

4. Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC 20057, USA

5. Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA

6. Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada

7. Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada

8. Department of BioMolecular Sciences, University of Mississippi, Oxford, MS 38677, USA

9. Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, Oxford, MS 38677, USA

10. Glycan Therapeutics, LLC, 617 Hutton Street, Raleigh, NC 27606, USA

Abstract

Local invasiveness of head and neck squamous cell carcinoma (HNSCC) is a complex phenomenon supported by interaction of the cancer cells with the tumor microenvironment (TME). We and others have shown that cancer-associated fibroblasts (CAFs) are a component of the TME that can promote local invasion in HNSCC and other cancers. Here we report that the secretory enzyme heparan-6-O-endosulfatase 2 (Sulf-2) directly affects the CAF-supported invasion of the HNSCC cell lines SCC35 and Cal33 into Matrigel. The Sulf-2 knockout (KO) cells differ from their wild type counterparts in their spheroid growth and formation, and the Sulf-2-KO leads to decreased invasion in a spheroid co-culture model with the CAF. Next, we investigated whether a fucosylated chondroitin sulfate isolated from the sea cucumber Holothuria floridana (HfFucCS) affects the activity of the Sulf-2 enzyme. Our results show that HfFucCS not only efficiently inhibits the Sulf-2 enzymatic activity but, like the Sulf-2 knockout, inhibits Matrigel invasion of SCC35 and Cal33 cells co-cultured with primary HNSCC CAF. These findings suggest that the heparan-6-O-endosulfatases regulate local invasion and could be therapeutically targeted with the inhibitory activity of a marine glycosaminoglycan.

Funder

National Institutes of Health

Publisher

MDPI AG

Subject

Cancer Research,Oncology

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