Pancreatic CAF-Derived Autotaxin Drives Autocrine CTGF Expression to Modulate Protumorigenic Signaling

Autotaxin (ATX), encoded by ENPP2, is a clinical target in pancreatic ductal adenocarcinoma (PDAC). ATX catalyzes the production of lysophosphatidic acid (LPA), an important regulator within the tumor microenvironment (TME), yet the protumorigenic action of the ATX/LPA axis in PDAC remains unclear. In this study, by interrogating patient samples and cell line datasets, we show that the PDAC TME, rather than cancer cells, is responsible for the majority of ENPP2 expression and highlight a key role for cancer-associated fibroblast (CAF)-derived ATX in autocrine and paracrine protumorigenic signaling. Using the clinical-stage ATX inhibitor, IOA-289, we identified connective tissue growth factor (CTGF), also known as CCN2, as a downstream mediator of ATX signaling in the PDAC CAF-derived cell line, 0082T. Genetic ablation or pharmacologic inhibition of ATX in 0082T CAFs reduced CTGF secretion via modulation of LPA/LPA receptor signaling. Despite the loss of ATX function, extracellular levels of LPA were paradoxically increased, indicating a role for ATX beyond its enzymatic activity and suggesting a role for its LPA chaperone function in the LPA/LPA receptor signaling in CAFs. As CAFs are the main source for CTGF in the PDAC TME, these findings suggest a role for ATX in promoting a protumorigenic microenvironment via modulation of CAF secretion not only via its LPA-producing activity but also via its LPA chaperone function, providing a potential mechanism for the antitumor effects of ATX inhibition.