Inhibition of adipose tissue-derived fatty acid binding protein suppresses pancreatic cancer progression and metastasis

Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, and obesity is a known risk factor for PDAC. Fatty acid binding protein 4 (FABP4) is noted to be higher in obese patients, and linked to the progression of obesity-related cancers. This study aimed to elucidate the role of FABP4 and the anticancer effect of FABP4 inhibition in PDAC using preclinical mouse models. Methods In mouse PDAC cells derived from genetic pancreatic cancer model with KRASG12D and p53 mutation, and human PDAC cell lines, we assessed cell viability, cellular proliferation, apoptosis, and invasion capability after FABP4 and/or FABP4 inhibitor (HTS01037) treatment. The antitumor effect of FABP4 inhibition was evaluated with syngeneic PDAC tumor in FABP4 null (AKO) mice as well as syngeneic and xenogeneic subcutaneous tumor models in mice treated with HTS01037. HTS01037 treatment was also tested in orthotopic as well as liver metastasis models. We analyzed epithelial-mesenchymal transition (EMT) and cancer stemness makers in vitro and vivo samples. In addition, efficacy of combination therapy of gemcitabine (GEM) plus HTS01037 was assessed in the syngeneic model. Results In vitro , HTS010137 suppressed FABP4-induced cell viability in human and murine PDAC cells. FABP4 increased cellular proliferation, and HTS01037 reversed the changes and increased apoptosis. FABP4 promoted migration and invasive potency, and increased EMT and stemness markers that were associated with up-regulation of EMT activating transcription factor ZEB1. Both FABP4 knockout and inhibition with HTS01037 suppressed the syngeneic subcutaneous tumor growth with reduction of EMT and stemness. Similar to the syngeneic tumors, the xenogeneic tumor growth was inhibited by HTS01037 treatment. HTS01037 showed significant anticancer and antimetastatic effect which improved the survivals in the orthotopic model. HTS01037 also attenuated development and growth of liver metastases in the liver metastasis model. Moreover, HTS01037 enhanced the efficacy of GEM to PDAC in vitro and in vivo . Conclusion FABP4 promoted the PDAC progression and FABP4 inhibition showed significant anticancer effect by suppressing cellular proliferation, EMT, and cancer stemness. FABP4 inhibitor has a promising translational value for PDAC treatment and can be a critical therapeutic option in PDAC patients.