PLIN5 affects the fibrosis and progression of pancreatic cancer via modulation of pancreatic stellate cells

AIMS: Pancreatic ductal adenocarcinoma (PDAC) develops therapy resistance primarily through its fibrotic stroma generated by activated pancreatic stellate cells (PSCs). While the lipid droplet protein perilipin 5 (PLIN5) may be associated with PSC quiescence, its precise role in PDAC pathogenesis remains unclear. This study aims to investigate PLIN5 role in regulating PSC function and tumor progression. METHODS: PLIN5 expression was analyzed in human PDAC tissue using immunohistochemistry and immunofluorescence. Primary and immortalized PSCs were used, and PLIN5 overexpression PSCs were created using lentiviral transfection. Subcutaneous and orthotopic pancreatic cancer models in nude mice were developed by using these PSCs and pancreatic cancer cells. Cytological assays, PCR, Western blotting and histological and immunofluorescence analysis, were performed to investigate PLIN5 expression in PSCs and its effects on PSC activation, fibrosis, and cancer progression. KEY FINDINGS: PLIN5 expression was markedly reduced in human PDAC tissues compared to normal adjacent pancreas and was specifically co-localized with α-SMA-positive stromal PSCs. PLIN5 expression is high in quiescent PSCs but is rapidly lost upon activation. PLIN5 inhibited PSC proliferation and migration, reduced extracellular matrix protein secretion, and restored lipid droplets formation. In vitro, PLIN5 overexpression PSCs significantly constrained the growth and invasive capacity of pancreatic cancer cells, w...