Extracellular Heparan 6-O-Endosulfatases SULF1 and SULF2 in Head and Neck Squamous Cell Carcinoma and Other Malignancies

Abstract

Pan-cancer analysis of TCGA and CPTAC (proteomics) data shows that SULF1 and SULF2 are oncogenic in a number of human malignancies and associated with poor survival outcomes. Our studies document a consistent upregulation of SULF1 and SULF2 in HNSC which is associated with poor survival outcomes. These heparan sulfate editing enzymes were considered largely functional redundant but single-cell RNAseq (scRNAseq) shows that SULF1 is secreted by cancer-associated fibroblasts in contrast to the SULF2 derived from tumor cells. Our RNAScope and patient-derived xenograft (PDX) analysis of the HNSC tissues fully confirm the stromal source of SULF1 and explain the uniform impact of this enzyme on the biology of multiple malignancies. In summary, SULF2 expression increases in multiple malignancies but less consistently than SULF1, which uniformly increases in the tumor tissues and negatively impacts survival in several types of cancer even though its expression in cancer cells is low. This paradigm is common to multiple malignancies and suggests a potential for diagnostic and therapeutic targeting of the heparan sulfatases in cancer diseases.

Heparan-6-O-endosulfatase 2 promotes invasiveness of head and neck squamous carcinoma cell lines in co-cultures with cancer associated fibroblasts

“…Sulf-1 [25,29] and Sulf-2 [29,45] are upregulated and oncogenic in multiple cancers [18,27,45,49], as we summarized recently [26]. Sulf-1 is typically not expressed in cancer cell lines and its overexpression may suppress cell growth [50].…”

“…Sulf-1 is typically not expressed in cancer cell lines and its overexpression may suppress cell growth [50]. However, Sulf-1 is commonly overexpressed in tumors [26]. We have documented [28] that cancer associated fibroblasts (CAF) supply Sulf-1 to the HNSC tumors [51], which explains the cancer cell-tumor discrepancy.…”

“…At the same time, high Sulf-1 in HNSCC and other cancers is associated with poor survival outcomes [26]. Sulf-2 is expressed primarily by epithelial cancer cells, is oncogenic in many cancers, and is associated with poor survival outcomes [26]. We have shown that Sulf-2 is upregulated and associated with poor survival outcomes in HNSCC [27,28].…”

“…Earlier studies correlated high levels of endogenous Sulf-1 and Sulf-2 with survival and tumorigenesis of hepatocellular carcinoma [18], pancreatic carcinoma [19], gastric carcinoma [20], invasive breast carcinoma [21], cervical carcinoma [22], urothelial carcinoma [23], glioblastoma [24], as well as in neoplasia [25]. We have shown that the Sulfs are upregulated in many cancers and negatively affect survival of HNSCC patients in a stage-specific manner [26]. Sulf-1 is supplied to the tumors primarily by the CAF, while Sulf-2 is more abundant in the epithelial HNSCC tumor cells [26–28].…”

“…We have shown that the Sulfs are upregulated in many cancers and negatively affect survival of HNSCC patients in a stage-specific manner [26]. Sulf-1 is supplied to the tumors primarily by the CAF, while Sulf-2 is more abundant in the epithelial HNSCC tumor cells [26–28]. The widespread upregulation of Sulfs in cancer and their impact on survival suggest that they should be explored as diagnostic and therapeutic targets [29].…”