Abstract C056: The prolyl isomerase PIN1 controls fibroblast state plasticity to impact pancreatic cancer

Abstract Pancreatic cancer associated fibroblasts (CAFs) have been described to play multiple, often conflicting, roles to support or restrict tumor growth. Recent work suggests that heterogeneous differentiation states of fibroblasts contribute to these diverse functions and that reprogramming of fibroblast states can influence tumor outcomes. The impact of distinct fibroblast subpopulations on heterogeneous tumor development and growth, however, remain incompletely understood. PIN1 is a phosphorylation-directed prolyl isomerase that alters the conformation and, therefore, the function of many proteins. PIN1 is overexpressed in cancer and contributes to cancer cell-intrinsic pro-tumorigenic behaviors including cellular proliferation and migration. While its pro-tumor functions have generated interest in therapeutic targeting of PIN1 for cancer treatment, the direct effects of PIN1 inhibition on tumor-associated stromal phenotypes are poorly understood. We have found that PIN1 loss or inhibition results in decreased tumor growth in vivo in transplant or genetically engineered mouse models. Moreover, in syngeneic orthotopic allograft models in which loss of PIN1 is restricted to the tumor host, we observed that KPC tumor cells still have decreased growth, suggesting a critical role for PIN1 in the tumor microenvironment. We observed that PIN1 loss or inhibition in vivo was accompanied by decreased expression of alpha-SMA, a marker of myofibroblast-like CAFs, and have identified a role for PIN1 in the phenotypic and epigenetic response to TGF-beta, a major driver of the myCAF state. PIN1low pancreatic stellate cells or CAFs display altered cell morphology, decreased proliferation, decreased ECM deposition, as well as altered paracrine signaling to cancer cells and other stromal cells. We are currently using 2D co-cultures, heterotypic 3D bioprinted tissues, and in vivo mouse models to interrogate the molecular mechanisms by which PIN1 controls fibroblast phenotypes and functional impact of altering fibroblast state on tumor phenotypes and outcomes. In addition, we are defining PIN1-dependent mechanisms of crosstalk between neoplastic and non-neoplastic cells and are investigating the requirements for specific fibroblast states to support in vivo growth of heterogeneous pancreatic cancer cells. Citation Format: Ellen M. Langer, Vidhi Shah, Amy Farrell, Colin Daniel, Xiaoyan Wang, Kevin MacPherson, Brittany L. Allen-Petersen, Motoyuki Tsuda, Mara Sherman, Andrew Adey, Rosalie C. Sears. The prolyl isomerase PIN1 controls fibroblast state plasticity to impact pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C056.