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Supplementary Figure S2 from Pancreatic CAF-Derived Autotaxin Drives Autocrine CTGF Expression to Modulate Protumorigenic Signaling

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posted on 2025-02-04, 08:21 authored by Fanny Volat, Ragini Medhi, Lauren Z. Maggs, Marcel A. Deken, Alice Price, Lauren Andrews, Jonathan Clark, Diane Taylor, Alan Carruthers, Ewan Taylor-Smith, Natalia Pacheco, Simon A. Rudge, Amy Fraser, Andrea F. Lopez-Clavijo, Bebiana C. Sousa, Zoë Johnson, Giusy Di Conza, Lars van der Veen, Pritom Shah, Hilary Sandig, Hayley J. Sharpe, Stuart Farrow

Supplementary Figure S2 shows the validation of 0082T CAF phenotype.

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Cancer Research UK Therapeutic Discovery Laboratories (CRUK-TDL)

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ARTICLE ABSTRACT

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.

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