Abstract 992: Pancreatic tuft cells resolve injury and restrain tumorigenesis
Authors: DelGiorno Kathleen E. , Chung Chi-Yeh , Ridinger Maya , Ali Wahida , Tsui Crystal , Ramos Cynthia , Ohmoto Makoto , Fang LinJing , Manor Uri , Matsumoto Ichiro , Wahl Geoffrey M. 
Published: August 2018

Pancreatic ductal adenocarcinoma (PDA) is the 3rd leading cause of cancer-related deaths in the United States and is predicted to be 2nd by the year 2020. The overall 5-year survival rate is &lt; 9% and median survival is only 4-6 months. Symptoms appear late in disease progression and metastasis has typically occurred by the time of diagnosis, making the study of early events in tumorigenesis essential. Intra-tumoral heterogeneity contributes to metastasis and engenders chemotherapeutic resistance in cancer. We have identified acinar-to-ductal metaplasia (ADM) as a source of heterogeneity in early pancreatic disease progression. ADM is the formation of highly reactive, dedifferentiated ducts from pancreatic acinar cells and is hypothesized to progress to pancreatic intraepithelial neoplasia (PanIN), a proposed precursor to PDA. Interestingly, we have identified phenotypically distinct cell populations in ADM, associated with both pancreatitis and PanIN, including a significant number of tuft cells. Tuft cells are solitary chemosensory cells found throughout the hollow organs of the respiratory and digestive tracts. Simultaneous expression of taste, inflammatory, and neuronal signaling pathways is thought to allow for monitoring of intraluminal content and local control of absorptive and secretory processes, though how they contribute to tissue injury and tumorigenesis remains a critical knowledge gap. Using imaging and sequencing techniques, as well as novel mouse models, we have found that tuft cells accumulate during chronic, caerulein-induced pancreatitis and form during the recovery phase of acute injury. Tuft cell ablation using Pou2f3 knockout mice significantly worsens chronic injury, including greater tissue loss and extracelluar matrix deposition, and impairs recovery. Similarly, tuft cell knockout mice experienced greater transformation and advanced tumorigenesis in a LSL-KrasG12D;Ptf1aCre/+ model of pancreatic tumorigenesis, suggesting that tuft cells abate disease progression. Tuft cell isolation and RNA sequencing revealed expression of several immune modulators including prostaglandin synthase Hpgds. We have found that treatment of primary pancreatic stellate cells and macrophages with Pgd2-family prostaglandins inhibits activation providing one mechanism by which tuft cells contribute to pancreatic disease and a possible therapeutic route to inhibit disease progression. In conclusion, chemosensory tuft cells form following tissue injury and in early pancreatic tumorigenesis and use paracrine signaling mechanisms to quell inflammation and ebb disease progression.

Citation Format: Kathleen E. DelGiorno, Chi-Yeh Chung, Maya Ridinger, Wahida Ali, Crystal Tsui, Cynthia Ramos, Makoto Ohmoto, LinJing Fang, Uri Manor, Ichiro Matsumoto, Geoffrey M. Wahl. Pancreatic tuft cells resolve injury and restrain tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 992.