The Prolyl Isomerase PIN1 Affects Fibroblast Differentiation States and Cross-talk in Pancreatic Cancer.

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. In this study, we showed that PIN1 is a critical regulator of pancreatic stellate cell (PSC) state at baseline and in response to the myofibroblast-activating factor TGFβ. Loss or inhibition of PIN1 altered the epigenetic and transcriptional responses of PSCs to TGFβ, preventing PSC differentiation to a myofibroblast state and altering expression of secreted matrix proteins and signaling molecules. Consistent with inhibition of the TGFβ response, low fibroblast PIN1 expression in mouse and human pancreatic ductal adenocarcinoma correlated with low expression of αSMA, a marker of myofibroblast activation. Decreased PIN1 expression at baseline also altered paracrine hepatocyte growth factor (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 cross-talk following PIN1 loss or inhibition, these data suggest that systemic targeting of PIN1 will suppress the protumorigenic pancreatic ductal adenocarcinoma microenvironment and may differentially affect heterogeneous patient populations. SIGNIFICANCE: PIN1 plays a critical role in the response of pancreatic stellate cells to TGFβ and can be targeted to attenuate myofibroblast activation and protumor cross-talk to suppress pancreatic cancer progression.