Tuft cells restrain pancreatic tumorigenesis through paracrine eicosanoid signaling

Tuft cells restrain pancreatic tumorigenesis through paracrine eicosanoid signaling. DelGiorno, K. E., Chung, C., Mauer, H. C., Novak, S. W., Giraddi, R. R., Wang, D., Naeem, R. F., Fang, L., Andrade, L. R., Lytle, N. K., Ali, W. H., Tsui, C., Gubbala, V. B., Ridinger-Saison, M., Ohmoto, M., O\textquoterightConnor, C., Erikson, G. A., Shokhirev, M. N., Urade, Y., Matsumoto, I., Vavinskaya, V., Singh, P. K., Manor, U., Olive, K. P., & Wahl, G. M. bioRxiv, Cold Spring Harbor Laboratory, 2019.

Paper doi abstract bibtex

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 to 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.Significance We find that tuft cell formation in response to oncogenic Kras is protective and restrains tumorigenesis through local production of anti-inflammatory substances, including paracrine prostaglandin D2 signaling to the stroma. Our findings establish tuft cells as a metaplasia-induced tumor suppressive cell type.

@article {DelGiorno2019.12.19.882985,
author = {Kathleen E. DelGiorno and Chi-Yeh Chung and H. Carlo Mauer and Sammy Weiser Novak and Rajshekhar R. Giraddi and Dezhen Wang and Razia F. Naeem and Linjing Fang and Leonardo R. Andrade and Nikki K. Lytle and Wahida H. Ali and Crystal Tsui and Vikas B. Gubbala and Maya Ridinger-Saison and Makoto Ohmoto and Carolyn O{\textquoteright}Connor and Galina A. Erikson and Maxim Nikolaievich Shokhirev and Yoshihiro Urade and Ichiro Matsumoto and Vera Vavinskaya and Pankaj K. Singh and Uri Manor and Kenneth P. Olive and Geoffrey M. Wahl},
title = {Tuft cells restrain pancreatic tumorigenesis through paracrine eicosanoid signaling},
elocation-id = {2019.12.19.882985},
year = {2019},
doi = {10.1101/2019.12.19.882985},
publisher = {Cold Spring Harbor Laboratory},
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 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 to 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.Significance We find that tuft cell formation in response to oncogenic Kras is protective and restrains tumorigenesis through local production of anti-inflammatory substances, including paracrine prostaglandin D2 signaling to the stroma. Our findings establish tuft cells as a metaplasia-induced tumor suppressive cell type.},
URL = {https://www.biorxiv.org/content/early/2019/12/20/2019.12.19.882985},
eprint = {https://www.biorxiv.org/content/early/2019/12/20/2019.12.19.882985.full.pdf},
journal = {bioRxiv}
}

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