Abstract 5169: Pancreatic tumorigenesis evokes mechanisms of tissue injury and repair

Abstract

Abstract Despite numerous advances in our understanding of pancreatic ductal adenocarcinoma (PDA) genetics and biology, this disease is expected to become the second leading cause of cancer-related deaths in the U.S. by 2020. These statistics largely reflect the fact that by the time PDA is detected, it has already spread, making the study of early events in tumorigenesis invaluable. Harold Dvorak is credited with suggesting that tumors behave as wounds that do not heal, specifically that they are able to induce the stroma required for their maintenance and growth. Decades of research have provided an array of molecular mechanisms supporting this hypothesis. When injured, the pancreas undergoes acinar to ductal metaplasia (ADM) where digestive enzyme-producing acinar cells transdifferentiate to ductal cells; a process thought to allow for tissue healing and repair. Though a number of insightful studies have been conducted to determine the underlying mechanisms of this process, it is still incompletely understood. Using a number of high-resolution imaging techniques and lineage tracing models, we have found that chronic pancreatic injury is sufficient to induce formation of a number of differentiated cell types during ADM, including tuft cells, which are absent from the normal pancreas and may function in tissue repair. Tuft cells are solitary chemosensory cells found throughout the hollow organs of the respiratory and digestive tracts. Their expression of taste, neuronal, and inflammatory cell signaling factors is thought to enable monitoring of intraluminal homeostasis and local response via effectors. Previous studies demonstrate that, in mice, tuft cells are absent from the normal pancreas, but transdifferentiate from the acinar cell epithelium in response to oncogenic Kras expression. Interestingly, while they increase during the genesis of pancreatic intraepithelial neoplasia (PanIN), they are not detected in PDA. Tuft cell formation is also characteristic of human pancreatitis and PanIN. These data suggest a conserved, transient, but currently undefined role for tuft cells in early tumorigenesis. Here, we employ novel mouse models to elucidate this role and to identify consequences of tuft cell ablation. These studies suggest that an important function of tuft cells involves production of immune-modulatory factors in response to injury and oncogenesis. Consistent with this, we show that pancreas-specific Pou2f3 ablation eliminates tuft cell formation and enhances disease progression. Collectively, these data suggest that neoplastic lesions that form in response to oncogenic mutation evoke the cellular heterogeneity that occurs during ADM in response to tissue injury. We conclude that tuft cells and, by inference, the associated metaplastic and neoplastic lesions, play a protective role early in pancreatic injury and tumorigenesis. Citation Format: Kathleen E. DelGiorno, Chi-Yeh Chung, Raj Giraddi, Eugene Ke, H. Carlo Maurer, Maya Ridinger-Saison, Wahida H. Ali, Crystal Tsui, Cynthia Ramos, Razia Naeem, Makoto Ohmoto, Linjing Fang, Gidsela Luna, Conor Fitzpatrick, Caz O'Connor, Uri Manor, Ichiro Matsumoto, Kenneth P. Olive, Geoffrey M. Wahl. Pancreatic tumorigenesis evokes mechanisms of tissue injury and repair [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5169.