Autotaxin Secretion Is a Stromal Mechanism of Adaptive Resistance to TGFβ Inhibition in Pancreatic Ductal Adenocarcinoma.

ABSTRACT: The TGFβ receptor inhibitor galunisertib demonstrated efficacy in patients with pancreatic ductal adenocarcinoma (PDAC) in the randomized phase II H9H-MC-JBAJ study, which compared galunisertib plus the chemotherapeutic agent gemcitabine with gemcitabine alone. However, additional stromal paracrine signals might confer adaptive resistance that limits the efficacy of this therapeutic strategy. Here, we found that autotaxin, a secreted enzyme that promotes inflammation and fibrosis by generating lysophosphatidic acid (LPA), mediates adaptive resistance to TGFβ receptor inhibition. Blocking TGFβ signaling prompted the skewing of cancer-associated fibroblasts (CAF) toward an inflammatory (iCAF) phenotype. iCAFs were responsible for a significant secretion of autotaxin. Paracrine autotaxin incr

SUBMITTER: Pietrobono S 

PROVIDER: S-EPMC10758691 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature