Abstract B028: Fibroblast PIN1 regulates growth factor and metabolic crosstalk to impact a subset of pancreatic cancer cells

Abstract

Abstract Pancreatic cancer associated fibroblasts (CAFs) 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. How distinct fibroblast subpopulations affect heterogeneous tumor development and growth, however, remains incompletely understood. PIN1 is a phosphorylation-directed prolyl isomerase that alters the conformation and, therefore, the function of many proteins. While PIN1 is known to be overexpressed in cancer and to contribute to cancer cell-intrinsic pro-tumorigenic behaviors, the direct effects of PIN1 inhibition on tumor-associated stromal phenotypes are poorly understood. We have identified a role for PIN1 in regulating fibroblast state and function. Loss or inhibition of PIN1 alters the epigenetic response to TGF-beta, resulting in lower expression of alpha-SMA, a marker of myofibroblast-like CAFs. PIN1 low pancreatic stellate cells (PSCs) or CAFs display decreased proliferation, decreased ECM deposition, and altered paracrine signaling to cancer cells and other stromal cells. In particular, HGF expression was markedly decreased in PIN1 low fibroblasts. Conditioned media from control PSCs was found to activate the MET receptor on cancer cells, driving changes consistent with an epithelial to mesenchymal transition, while conditioned media from shPIN1 PSCs failed to drive these changes. In vivo loss or inhibition of PIN1 significantly decreased tumor growth in multiple mouse models, and consistent with our in vitro data, the smaller lesions in the autochthonous PIN1 knockout KPC mice also displayed decreased expression of alpha-SMA and decreased activation of pMET. To determine the impact of stromal PIN1 on tumor growth, we orthotopically injected KPC pancreatic tumor cell lines into syngeneic PIN1 wildtype or knockout hosts. We found that growth of some cell lines (e.g. KPC8060) were significantly reduced in PIN1 knockout compared to wildtype hosts, while growth of other cells (e.g. KPC7107) were similar in PIN1 wildtype and knockout hosts. In vitro, we found that the KPC8060 cell line increased proliferation and lactate production in response to exogenous HGF, while the KPC7107 cell line did not. This work supports a model in which a subset of pancreatic tumors depends on crosstalk from PIN1 expressing fibroblasts in the tumor microenvironment. We are currently using 2D co-cultures, heterotypic 3D bioprinted tissues, and in vivo mouse models to further understand how PIN1 loss in fibroblasts influences the full tumor microenvironment and to further characterize the dependency of heterogenous pancreatic cancer cells on specific components from a PIN1 sufficient microenvironment. Citation Format: Chloe L. Bowman, Eric J. Carlson, Vidhi Shah, Colin J. Daniel, Xiaoyan Wang, Motoyuki Tsuda, Rosalie C. Sears, Ellen M. Langer. Fibroblast PIN1 regulates growth factor and metabolic crosstalk to impact a subset of pancreatic cancer cells [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B028.