LAUSR

Simple Summary 6-O-endosulfatases, SULF1 and SULF2, are oncogenic in multiple malignancies and are associated with poor survival outcomes. SULF1 is one of the most consistently unregulated enzymes in HNSCC tissues even though its expression in the cancer cells is marginal. Our PDX and RNA scope experiments confirm that SULF1 is provided to the tissues by cancer-associated fibroblasts as opposed to SULF2 supplied by the cancer cells. This paradigm is common to multiple malignancies and suggests a potential for diagnostic and therapeutic targeting of the heparin sulfatases in cancer diseases. 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.