High intrapancreatic fat deposition accelerates pancreatic ductal adenocarcinoma growth and metastasis with enrollment of FABP5 upregulation

A prospective observational study has shown that intrapancreatic fat deposition (IPFD) increases pancreatic ductal adenocarcinoma (PDAC) risk; however, the underlying mechanisms remain unclear. In this study, we established a C57BL/6J mouse model of IPFD by feeding them Gubra Amylin NASH (GAN), a high-fat diet, to evaluate the effect of IPFD on PDAC. Mice in the GAN 30-week group exhibited significantly higher IPFD than controls. RNA sequencing of pancreatic tissue from this group revealed increased fatty acid-binding protein (FABP) 5 and MKI67 expression, along with an upregulation of the JAK/STAT, PI3K/AKT/mTOR, and Ras/Raf/MEK/ERK signaling pathways. In a syngeneic orthotopic PDAC mouse model using KPC cells, mice fed a GAN diet showed rapid tumor growth, a high incidence of liver metastasis, and intraperitoneal dissemination. In vitro, FABP5 promoted PDAC cell proliferation and migration by upregulating RAC1, a Rho family small GTPase associated with cellular movement. Inhibition of FABP5 using BMS-309,403 suppressed syngeneic KPC subcutaneous tumor growth without serious side effects. Conclusively, this study demonstrates that high IPFD enhances PDAC carcinogenesis, growth, and metastasis with enrollment of FABP5 upregulation, indicating that FABP5 inhibition may represent a potential therapeutic strategy for PDAC.