Fernandez-Barena, Maite

Abstract The role of the transcription factor GLI1 in pancreatic tumor initiation promoting the progression of preneoplastic lesions into tumors is well established. However, its function at later stages of pancreatic carcinogenesis remains poorly understood. To address this issue, we crossed the GLI1 knockout animal (GKO) with cre-dependent pancreatic activation of oncogenic KRAS concomitant with loss of the tumor suppressor TP53 (KPC). Interestingly, in this model, GLI1 played a tumor protective function, where survival of GKO/KPC mice was reduced compared to KPC littermates. Both cohorts developed pancreatic cancer without significant histopathological differences in survival studies. However, analysis of mice using ultrasound-based imaging at earlier time-points showed increased tumor burden in GKO/KPC mice. These animals have larger tumors, decreased body weight, increased lactate dehydrogenase production, and leukopenia. Expression studies identified FAS and FAS ligand as potential mediators of this phenomenon. The FAS /FASL axis, an apoptotic inducer, plays a role in the progression of pancreatic cancer, where its expression is usually lost or significantly reduced in advanced stages of the disease. Chromatin immunoprecipitation assays identified FAS and FASL as direct targets of GLI1 where GKO/KPC mice showed lower levels of this ligand compared to KPC animals. Furthermore, GLI1 overexpression and knockdown studies demonstrate a key regulatory role for GLI1 in both FAS and FASL expression. Finally, decreased levels of apoptosis were detected in the tumor tissue in the absence of GLI1 by TUNEL staining. Together, these findings define a novel pathway regulated by GLI1 controlling pancreatic tumor progression and provide a new theoretical framework to help the design and analysis of trials targeting GLI1-related pathways. Citation Format: Lisa D. Mills, Lizhi Zhang, Ronald J. Marler, Phyllis A. Svingen, Maite Fernandez-Barena, Maneesh Dave, William Bamlet, Robert McWilliams, William A. Faubion, Martin E. Fernandez-Zapico. Loss of GLI1 accelerates pancreatic cancer progression in the KPC mouse model. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A76.