The Prolyl Isomerase PIN1 Impacts Fibroblast Differentiation States and Crosstalk in Pancreatic Cancer

Abstract The prolyl isomerase PIN1 is overexpressed in cancer and contributes to cancer cell-intrinsic phenotypes including proliferation and migration. However, PIN1 may also function in stromal cells within the tumor microenvironment (TME). Here, we showed that PIN1 is a critical regulator of pancreatic stellate cell (PSC) state at baseline and in response to the myofibroblast activating factor TGF-β. Loss or inhibition of PIN1 altered the epigenetic and transcriptional response of PSCs to TGF-β, preventing PSC differentiation to a myofibroblast state and altering expression of secreted matrix proteins and signaling molecules. Consistent with inhibition of the TGF-β response, low fibroblast PIN1 expression in mouse and human pancreatic ductal adenocarcinoma (PDAC) correlated with low expression of α-SMA, a marker of myofibroblast activation. Decreased PIN1 expression at baseline also altered paracrine HGF signaling from fibroblasts to tumor cells. PSCs with low PIN1 expression displayed reduced expression and secretion of HGF, resulting in an attenuation of c-MET receptor phosphorylation and signaling in nearby cancer cells. In allograft models, host PIN1 was critical for normal growth of a subset of pancreatic cancer cell lines that are responsive to HGF signaling. Through the identification of changes to fibroblast activation state and crosstalk following PIN1 loss or inhibition, these data suggest that systemic targeting of PIN1 will suppress the pro-tumorigenic PDAC microenvironment and may differentially affect heterogeneous patient populations.