The Prolyl Isomerase PIN1 Plays a Critical Role in Fibroblast Differentiation States to Support Pancreatic Cancer

The prolyl isomerase PIN1 is overexpressed in cancer and contributes to cancer cell-intrinsic phenotypes including proliferation and migration. While its pro-tumor role has generated interest in targeting PIN1, its role in tumor-associated stromal phenotypes has not yet been studied. Here, we show that in addition to contributing to intrinsic tumor cell phenotypes, PIN1 is a critical regulator of fibroblast differentiation states. Loss of PIN1 in pancreatic stellate cells, the primary cells responsible for stromal expansion in pancreatic tumors, impairs the epigenetic response to TGF β and activation to a myofibroblast state, driving instead an antigen presenting fibroblast state. This shift in fibroblast function with PIN1 loss alters the tumor ecosystem, resulting in reduced paracrine HGF signaling to cancer cells, reduced extracellular matrix deposition, and increased vascularization. This work defines a role for PIN1 in controlling fibroblast function and suggests that targeting PIN1 in cancer will have a broad anti-tumor effect.