Matthew Gk Benesch, Rongrong Wu, Xiaoyun Tang, David N Brindley, Takashi Ishikawa, Kazuaki Takabe
Autotaxin (ATX) is a secreted enzyme that produces extracellular lysophosphatidate in physiological wound healing. ATX is overexpressed in many cancers to promote growth, metastasis, and treatment resistance. However, ATX expression is very low in breast cancer cells, and is instead secreted by the tumor microenvironment (TME). Paracrine ATX expression, and its effects on tumor progression, has not been robustly studied in human breast tumors. In this study, ATX expression was analyzed in over 5000 non-metastatic breast cancers from databases TCGA, METABRIC and GSE96058, dichotomized by the median. Gene set enrichment analysis (GSEA) and the xCell algorithm investigated biological functions of ATX and correlation to TME cell populations. TME ATX production was verified by single cell RNA sequencing. The highest ATX expression occurred in endothelial cells and cancer-associated fibroblasts (<0.0001). High tumor ATX expression correlated to increased adipocyte, fibroblast, and endothelial cell fractions (<0.01), and GSEA demonstrated enriched immune system, tumor suppressor, pro-survival, stemness, and pro-inflammatory signaling in multiple gene sets. Tumor mutational burden was decreased, Ki67 scores were decreased, tumor infiltrating immune cell populations increased, and immune cytolytic activity scores increased (all <0.01) for ATX-high tumors. Overall survival trends favored ATX-high tumors (hazard ratios 0.75-0.80). In summary, in human breast cancers, ATX is produced by the TME, and in non-metastatic tumors, high levels correlate with an anti-tumor phenotype. Because pre-clinical models use aggressive pro-metastatic cell lines where ATX-mediated signaling promotes tumorigenesis, further research is required to verify an anti-to-pro-tumor phenotype switch with breast cancer progression and/or treatment resistance.
