Tuft cells restrain pancreatic tumorigenesis through paracrine eicosanoid signaling
Kathleen E. DelGiorno,
H. Carlo Mauer,
Sammy Weiser Novak,
Rajshekhar R Giraddi,
Razia F. Naeem,
Leonardo R. Andrade,
Nikki K. Lytle,
Wahida H. Ali,
Vikas B. Gubbala,
Galina A. Erikson,
Maxim Nikolaievich Shokhirev,
Pankaj K Singh,
Kenneth P. Olive,
Geoffrey M Wahl
Posted 20 Dec 2019
bioRxiv DOI: 10.1101/2019.12.19.882985
Posted 20 Dec 2019
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 U.S. deaths within the next few years. Incomplete understanding of how it arises precludes development of early detection and interception strategies to improve therapeutic outcomes. Acinar-ductal metaplasia involving genesis of tuft cells is one early step in PDA formation, but their functional significance has remained obscure due to their rarity and a lack of methods and relevant animal models for their molecular and functional analysis. Here, we show that deletion of tuft cell master regulator Pou2f3 eliminates pancreatic tuft cells and increases fibrosis, alters immune cell activation, and accelerates disease progression. We demonstrate that tuft cell expression of the prostaglandin D2 synthase Hpgds restrains pancreatic disease progression in early stages by inhibiting stromal activation. Analyses of human data sets are consistent with mouse studies. We propose that tuft cells and, by inference, the associated metaplastic lesions, play a protective role early in pancreatic tumorigenesis.
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